Biaryl Heterocyclic Compounds and Methods of Making and Using the Same

ABSTRACT

The present invention relates generally to the field of anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of compounds having both a biaryl moiety and at least one heterocylic moiety that are useful as such agents.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/240,297, filed Sep. 22, 2011, which is a continuation of U.S. patentapplication Ser. No. 12/767,380, filed Apr. 26, 2010, which is acontinuation of U.S. patent application Ser. No. 12/275,941, filed Nov.21, 2008, which issued as U.S. Pat. No. 7,705,026 on Apr. 27, 2010,which is a continuation of U.S. patent application Ser. No. 11/486,769,filed Jul. 14, 2006, which issued as U.S. Pat. No. 7,456,206 on Nov. 25,2008, which is a continuation of U.S. patent application Ser. No.11/118,808, filed Apr. 29, 2005, which issued as U.S. Pat. No. 7,148,219on Dec. 12, 2006, which is a continuation of U.S. patent applicationSer. No. 10/859,476, filed Jun. 2, 2004, which issued as U.S. Pat. No.6,969,726 on Nov. 29, 2005, which claims the benefit of and priority toU.S. Patent Application Nos. 60/475,430, filed Jun. 3, 2003; 60/475,453,filed Jun. 3, 2003; 60/490,855, filed Jul. 29, 2003; 60/529,731, filedDec. 15, 2003; and 60/531,584, filed Dec. 19, 2003, the disclosures ofwhich are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective,anti-proliferative, anti-inflammatory, and prokinetic agents. Moreparticularly, the invention relates to a family of biaryl heterocycliccompounds, comprising both a biaryl moiety and at least one heterocyclicmoiety, that are useful as therapeutic agents.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once believed that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such beliefs have been shaken by thefact that strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. In fact, virtuallyevery antibiotic agent developed for clinical use has ultimatelyencountered problems with the emergence of resistant bacteria. Forexample, resistant strains of Gram-positive bacteria such asmethicillin-resistant staphylocci, penicillin-resistant streptococci,and vancomycin-resistant enterococci have developed, which can causeserious and even fatal results for patients infected with such resistantbacteria. Bacteria that are resistant to macrolide antibiotics, i.e.,antibiotics based on a 14- to 16-membered lactone ring, have developed.Also, resistant strains of Gram-negative bacteria such as H. influenzaeand M. catarrhalis have been identified. See, e.g., F. D. Lowry,“Antimicrobial Resistance: The Example of Staphylococcus aureus,” J.Clin. Invest., 2003, 111(9), 1265-1273; and Gold, H. S. and Moellering,R. C., Jr., “Antimicrobial-Drug Resistance,” N. Engl. J. Med., 1996,335, 1445-53.

The problem of resistance is not limited to the area of anti-infectiveagents, because resistance has also been encountered withanti-proliferative agents used in cancer chemotherapy. Therefore, thereexists a need for new anti-infective and anti-proliferative agents thatare both effective against resistant bacteria and resistant strains ofcancer cells.

In the antibiotic area, despite the problem of increasing antibioticresistance, no new major classes of antibiotics have been developed forclinical use since the approval in the United States in 2000 of theoxazolidinone ring-containing antibiotic,N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methylacetamide, which is known as linezolid and is sold under the tradenameZyvox® (see compound A). See, R. C. Moellering, Jr., “Linezolid: TheFirst Oxazolidinone Antimicrobial,” Annals of Internal Medicine, 2003,138(2), 135-142.

Linezolid was approved for use as an anti-bacterial agent active againstGram-positive organisms. Unfortunately, linezolid-resistant strains oforganisms are already being reported. See, Tsiodras et al., Lancet,2001, 358, 207; Gonzales et al., Lancet, 2001, 357, 1179; Zurenko etal., Proceedings Of The 39^(th) Annual Interscience Conference OnAntibacterial Agents And Chemotherapy (ICAAC); San Francisco, Calif.,USA, (Sep. 26-29, 1999). Because linezolid is both a clinicallyeffective and commercially significant anti-microbial agent,investigators have been working to develop other effective linezolidderivatives.

Notwithstanding the foregoing, there is an ongoing need for newanti-infective and anti-proliferative agents. Furthermore, because manyanti-infective and anti-proliferative agents have utility asanti-inflammatory agents and prokinetic agents, there is also an ongoingneed for new compounds useful as anti-inflammatory and prokineticagents.

SUMMARY OF THE INVENTION

The invention provides a family of compounds useful as anti-infectiveagents and/or anti-proliferative agents, for example, chemotherapeuticagents, anti-microbial agents, anti-bacterial agents, anti-fungalagents, anti-parasitic agents, anti-viral agents, anti-inflammatoryagents, and/or prokinetic (gastrointestinal modulatory) agents. Thecompounds have the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinHet-CH₂—R⁴ is selected from the group consisting of:

A and B independently are selected from the group consisting of phenyl,pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; M-L is selected fromthe group consisting of M-X, M-L¹, M-L¹-X, M-X-L², M-L¹-X-L²,M-X-L¹-X-L², M-L¹-X-L²-X, M-X—X—, M-L¹-X—X—, M-X—X-L², and M-L¹-X—X-L²;M is an optionally substituted saturated, unsaturated, or aromatic C₃₋₁₄carbocycle, or an optionally substituted saturated, unsaturated, oraromatic 3-14 membered heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur; andthe variables L¹, L², M, R¹, R², R³, X, m, and n are selected from therespective groups of chemical moieties or integers later defined in thedetailed description.

Particular embodiments of compounds of the invention include thosehaving the formula:

wherein the variables A, L, M, R¹, R³, and m are selected from therespective groups of chemical moieties or integers later defined in thedetailed description.

In addition, the invention provides methods of synthesizing theforegoing compounds. Following synthesis, an effective amount of one ormore of the compounds may be formulated with a pharmaceuticallyacceptable carrier for administration to a mammal for use as ananti-cancer, anti-microbial, anti-biotic, anti-fungal, anti-parasitic oranti-viral agent, or to treat a proliferative disease, an inflammatorydisease or a gastrointestinal motility disorder. The compounds orformulations may be administered, for example, via oral, parenteral, ortopical routes, to provide an effective amount of the compound to themammal.

The foregoing and other aspects and embodiments of the invention may bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used asanti-proliferative agents and/or anti-infective agents. The compoundsmay be used without limitation, for example, as anti-cancer,anti-microbial, anti-bacterial, anti-fungal, anti-parasitic and/oranti-viral agents. Further, the present invention provides a family ofcompounds that can be used without limitation as anti-inflammatoryagents, for example, for use in treating chronic inflammatory airwaydiseases, and/or as prokinetic agents, for example, for use in treatinggastrointestinal motility disorders such as gastroesophageal refluxdisease, gastroparesis (diabetic and post surgical), irritable bowelsyndrome, and constipation.

1. Definitions

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g., C═C, C═N, or N═N).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

The compounds described herein may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention.

When any variable (e.g., R¹) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R¹ moieties,then the group may optionally be substituted with up to two R¹ moietiesand R¹ at each occurrence is selected independently from the definitionof R¹. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

Compounds of the present invention that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g., MCPBAand/or hydrogen peroxides) to afford other compounds of the presentinvention. Thus, all shown and claimed nitrogen-containing compounds areconsidered, when allowed by valency and structure, to include both thecompound as shown and its N-oxide derivative (which can be designated asN→O or N⁺—O⁻). Furthermore, in other instances, the nitrogens in thecompounds of the present invention can be converted to N-hydroxy orN-alkoxy compounds. For example, N-hydroxy compounds can be prepared byoxidation of the parent amine by an oxidizing agent such as MCPBA. Allshown and claimed nitrogen-containing compounds are also considered,when allowed by valency and structure, to cover both the compound asshown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein Ris substituted or unsubstituted C₁₋₆ alkyl, alkenyl, alkynyl, C₃₋₁₄carbocycle, or 3-14-membered heterocycle) derivatives.

When an atom or chemical moiety is followed by a subscripted numericrange (e.g., C₁₋₆), the invention is meant to encompass each numberwithin the range as well as all intermediate ranges. For example, “C₁₋₆alkyl” is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5,1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6carbons.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or morecarbon-carbon double bonds occurring at any stable point along thechain. For example, C₂₋₆ alkenyl is intended to include C₂, C₃, C₄, C₅,and C₆ alkenyl groups. Examples of alkenyl include, but are not limitedto, ethenyl and propenyl.

As used herein, “alkynyl” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or morecarbon-carbon triple bonds occurring at any stable point along thechain. For example, C₂₋₆ alkynyl is intended to include C₂, C₃, C₄, C₅,and C₆ alkynyl groups. Examples of alkynyl include, but are not limitedto, ethynyl and propynyl.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic ring” is intended to meanany stable monocyclic, bicyclic, or tricyclic ring having the specifiednumber of carbons, any of which may be saturated, unsaturated, oraromatic. For example a C₃₋₁₄ carbocycle is intended to mean a mono-,bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14carbon atoms. Examples of carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are alsoincluded in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. Preferred bridges are one ortwo carbon atoms. It is noted that a bridge always converts a monocyclicring into a tricyclic ring. When a ring is bridged, the substituentsrecited for the ring may also be present on the bridge. Fused (e.g.,naphthyl and tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term “heterocycle” or “heterocyclic” is intended tomean any stable monocyclic, bicyclic, or tricyclic ring which issaturated, unsaturated, or aromatic and comprises carbon atoms and oneor more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from the group consisting ofnitrogen, oxygen, and sulfur. A bicyclic or tricyclic heterocycle mayhave one or more heteroatoms located in one ring, or the heteroatoms maybe located in more than one ring. The nitrogen and sulfur heteroatomsmay optionally be oxidized (i.e., N→O and S(O)_(p), where p=1 or 2).When a nitrogen atom is included in the ring it is either N or NH,depending on whether or not it is attached to a double bond in the ring(i.e., a hydrogen is present if needed to maintain the tri-valency ofthe nitrogen atom). The nitrogen atom may be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, asdefined). The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. Bridged rings are alsoincluded in the definition of heterocycle. A bridged ring occurs whenone or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon ornitrogen atoms. Preferred bridges include, but are not limited to, onecarbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms,and a carbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.Spiro and fused rings are also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicaromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclicaromatic heterocyclic ring which consists of carbon atoms and one ormore heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclicaromatic rings, only one of the two rings needs to be aromatic (e.g.,2,3-dihydroindole), though both may be (e.g., quinoline). The secondring can also be fused or bridged as defined above for heterocycles. Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines, alkali or organic salts ofacidic residues such as carboxylic acids, and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of the presentinvention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” means the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

As used herein, “mammal” refers to human and non-human patients.

As used herein, the term “effective amount” refers to an amount of acompound, or a combination of compounds, of the present inventioneffective when administered alone or in combination as ananti-proliferative and/or anti-infective agent. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22:27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedanti-proliferative and/or anti-infective effect, or some otherbeneficial effect of the combination compared with the individualcomponents.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where processes are described as having,including, or comprising specific process steps, the processes alsoconsist essentially of, or consist of, the recited processing steps.Further, it should be understood that the order of steps or order forperforming certain actions are immaterial so long as the inventionremains operable. Moreover, two or more steps or actions may beconducted simultaneously.

2. Compounds of the Invention

In one aspect, the invention provides compounds having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein:

A is selected from the group consisting of:

-   -   phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

B is selected from the group consisting of:

-   -   phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

Het-CH₂—R³ is selected from the group consisting of:

M is selected from the group consisting of:

-   -   a) saturated, unsaturated, or aromatic C₃₋₁₄ carbocycle, and b)        saturated, unsaturated, or aromatic 3-14 membered heterocycle        containing one or more heteroatoms selected from the group        consisting of nitrogen, oxygen, and sulfur,        -   wherein a) or b) optionally is substituted with one or more            R⁵ groups;

M-L is selected from the group consisting of:

-   -   a) M-X, b) M-L¹, c) M-L¹-X, d) M-X-L², e) M-L¹-X-L², f)        M-X-L¹-X-L², g) M-L¹-X-L²-X, h) M-X—X—, i) M-L¹-X—X—, j)        M-X—X-L², and k) M-L¹-X—X-L², wherein    -   X, at each occurrence, independently is selected from the group        consisting of:        -   a) —O—, b) —NR⁴—, c) —N(O)—, d) —N(OR⁴)—, e) —S(O)_(p)—, f)            —SO₂NR⁴—, g) —NR⁴SO₂—, h) —NR⁴—N═, i) ═N—NR⁴—, j) —O—N═, k)            ═N—O—, l) —N═, m) ═N—, n) —NR⁴—NR⁴—, o) —NR⁴C(O)O—, p)            —OC(O)NR⁴—, q) —NR⁴C(O)NR⁴— r) —NR⁴C(NR⁴)NR⁴—, and s)

-   -   L¹ is selected from the group consisting of:        -   a) C₁₋₆ alkyl, b) C₂₋₆ alkenyl, and c) C₂₋₆ alkynyl, wherein            any of a)-c) optionally is substituted with one or more R⁵            groups; and

L² is selected from the group consisting of:

-   -   a) C₁₋₆ alkyl, b) C₂₋₆ alkenyl, and c) C₂₋₆ alkynyl,        -   wherein any of a)-c) optionally is substituted with one or            more R⁵ groups;

R¹, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i)        —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n)        —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)        —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v)        —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z)        —NR⁴C(NR⁴)NR⁴R⁴, aa) —S(O)_(p)R⁴, bb) —SO₂NR⁴R⁴, and cc) R⁴;

R², at each occurrence, independently is selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i)        —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n)        —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)        —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v)        —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z)        —NR⁴C(NR⁴)NR⁴R⁴, aa) —S(O)_(p)R⁴, bb) —SO₂NR⁴R⁴, and cc) R⁴;

R³ is selected from the group consisting of:

-   -   a) —OR⁴, b) —NR⁴R⁴, c) —C(O)R⁴, d) —C(O)OR⁴, e) —OC(O)R⁴, f)        —C(O)NR⁴R⁴, g) —NR⁴C(O)R⁴, h) —OC(O)NR⁴R⁴, i) —NR⁴C(O)OR⁴, j)        —NR⁴C(O)NR⁴R⁴, k) —C(S)R⁴, l) —C(S)OR⁴, m) —OC(S)R⁴, n)        —C(S)NR⁴R⁴, o) —NR⁴C(S)R⁴, p) —OC(S)NR⁴R⁴, q) —NR⁴C(S)OR⁴, r)        —NR⁴C(S)NR⁴R⁴, s) —NR⁴C(NR⁴)NR⁴R⁴, t) —S(O)_(p)R⁴, u) —SO₂NR⁴R⁴,        and v) R⁴;

R⁴, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) H, b) C₁₋₆ alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e) C₃₋₁₄        saturated, unsaturated, or aromatic carbocycle, f) 3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur, g) —C(O)—C₁₋₆ alkyl, h) —C(O)—C₂₋₆        alkenyl, i) —C(O)—C₂₋₆ alkynyl, j) —C(O)—C₃₋₁₄ saturated,        unsaturated, or aromatic carbocycle, k) —C(O)-3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur, l) —C(O)O—C₁₋₆ alkyl, m)        —C(O)O—C₂₋₆ alkenyl, n) —C(O)O—C₂₋₆ alkynyl, o) —C(O)O—C₃₋₁₄        saturated, unsaturated, or aromatic carbocycle, and p)        —C(O)O-3-14 membered saturated, unsaturated, or aromatic        heterocycle comprising one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of b)-p) optionally is substituted with one or            more R⁵ groups;

R⁵, at each occurrence, is independently selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁶, h) ═NOR⁶, i)        ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l) —CN, m) —NO₂, n) —NR⁶R⁶, o)        —C(O)R⁶, p) —C(O)OR⁶, q) —OC(O)R⁶, r) —C(O)NR⁶R⁶, s)        —NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u) —NR⁶C(O)OR⁶, v) —NR⁶C(O)NR⁶R⁶, w)        —C(S)R⁶, x) —C(S)OR⁶, y) —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa)        —NR⁶C(S)R⁶, bb) —OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶,        ee) —NR⁶C(NR⁶)NR⁶R⁶, ff) —S(O)_(p)R⁶, gg) —SO₂NR⁶R⁶, and hh) R⁶;

R⁶, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) H, b) C₁₋₆ alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e) C₃₋₁₄        saturated, unsaturated, or aromatic carbocycle, f) 3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur, g) —C(O)—C₁₋₆ alkyl, h) —C(O)—C₂₋₆        alkenyl, i) —C(O)—C₂₋₆ alkynyl, j) —C(O)—C₃₋₁₄ saturated,        unsaturated, or aromatic carbocycle, k) —C(O)-3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur, l) —C(O)O—C₁₋₆ alkyl, m)        —C(O)O—C₂₋₆ alkenyl, n) —C(O)O—C₂₋₆ alkynyl, o) —C(O)O—C₃₋₁₄        saturated, unsaturated, or aromatic carbocycle, and p)        —C(O)O-3-14 membered saturated, unsaturated, or aromatic        heterocycle comprising one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of b)-p) optionally is substituted with one or            more R⁷ groups;

R⁷, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h) ═NOR⁸, i)        ═N—NR⁸R⁸, j) —CF₃, k) —OR⁸, l) —CN, m) —NO₂, n) —NR⁸R⁸, o)        —C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r) —C(O)NR⁸R⁸, s)        —NR⁸C(O)R⁸, t) —OC(O)NR⁸R⁸, u) —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w)        —C(S)R⁸, x) —C(S)OR⁸, y) —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa)        —NR⁸C(S)R⁸, bb) —OC(S)NR⁸R⁸, cc) —NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸,        ee) —NR⁸C(NR⁸)NR⁸R⁸, ff) —S(O)_(p)R⁸, gg) —SO₂NR⁸R⁸, hh) C₁₋₆        alkyl, ii) C₂₋₆ alkenyl, jj) C₂₋₆ alkynyl, kk) C₃₋₁₄ saturated,        unsaturated, or aromatic carbocycle, and ll) 3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur,        -   wherein any of hh)-ll) optionally is substituted with one or            more moieties selected from the group consisting of R⁸, F,            Cl, Br, I, —CF₃, —OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸,            —C(O)OR⁸, —OC(O)R⁸, —C(O)NR⁸R⁸, —NR⁸C(O)R⁸, —OC(O)NR⁸R⁸,            —NR⁸C(O)OR⁸, —NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸, —OC(S)R⁸,            —C(S)NR⁸R⁸, —NR⁸C(S)R⁸, —OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸,            —NR⁸C(S)NR⁸R⁸, —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸, and —S(O)_(p)R⁸;

R⁸, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) H, b) C₁₋₆ alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e) C₃₋₁₄        saturated, unsaturated, or aromatic carbocycle, f) 3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur, g) —C(O)—C₁₋₆ alkyl, h) —C(O)—C₂₋₆        alkenyl, i) —C(O)—C₂₋₆ alkynyl, j) —C(O)—C₃₋₁₄ saturated,        unsaturated, or aromatic carbocycle, k) —C(O)-3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur, l) —C(O)O—C₁₋₆ alkyl, m)        —C(O)O—C₂₋₆ alkenyl, n) —C(O)O—C₂₋₆ alkynyl, o) —C(O)O—C₃₋₁₄        saturated, unsaturated, or aromatic carbocycle, and p)        —C(O)O-3-14 membered saturated, unsaturated, or aromatic        heterocycle comprising one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of b)-p) optionally is substituted with one or            more moieties selected from the group consisting of F, Cl,            Br, I, —CF₃, —OH, —OCH₃, —SH, —SCH₃, —CN, —NO₂, —NH₂,            —NHCH₃, —N(CH₃)₂, —C(O)CH₃, —C(O)OCH₃, —C(O)NH₂, —NHC(O)CH₃,            —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, and —S(O)_(p)CH₃;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p, at each occurrence, independently is 0, 1, or 2,

and wherein the compound does not have the formula corresponding to anyof the structures listed in Table 1.

TABLE 1

Particular embodiments of the invention include compounds having theformula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, B, L, M, R¹, R², R³, m, and n are defined above.

Other embodiments include compounds having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, B, L, M, R¹, R², R³, m, and n are defined as described above.

Particular compounds include those where A is selected from the groupconsisting of phenyl and pyridyl; B is selected from the groupconsisting of phenyl and pyridyl; m is 0, 1, or 2; and n is 0, 1, or 2.

In some embodiments, A-B is:

wherein A, R², and n are defined as described above. In particularembodiments, A-B is:

wherein A is defined as described above.

In various embodiments, A-B is:

wherein B is defined as described in above.

In some embodiments, R³ is —NHC(O)R⁴. Particular compounds according tothese embodiments include those where R⁴ is —CH₃ or

Particular embodiments of the invention include compounds having theformula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, B, L, M, R¹, R², m, and n are defined as described above.

Other embodiments of the invention include compounds having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, L, M, R¹, R³, and m are defined as described above.

Still other embodiments of the invention include compounds having theformula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, L, M, R¹, and m are defined as described above.

Some embodiments of the invention include compounds having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinL, M, and R³ are defined as described above. Particular compoundsaccording to these embodiments include those wherein R³ is —NHC(O)CH₃.

Other embodiments of the invention include compounds having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, L, M, R¹, R³, and m are defined as described above.

Still other embodiments of the invention include compounds having theformula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, L, M, R¹, and m are defined as described above.

Some embodiments of the invention include compounds having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinL, M, and R³ are defined as described above. Particular compoundsaccording to these embodiments include those wherein R³ is —NHC(O)CH₃.

In some embodiments, M-L is M-L¹, and L¹ is C₁₋₆ alkyl. In particularembodiments, M-L¹ is M-CH₂—.

In other embodiments, M-L is M-L¹-X-L², and X is —NR⁴—. In particularcompounds according to these embodiments, X is —NH—, —N(O)—, or—N(OR⁴)—, where R⁴ is H or C₁₋₆ alkyl. Other compounds include thosewhere X is

In certain compounds according to these embodiments, L¹ is C₁₋₆ alkyl,and L² is C₁₋₆ alkyl. In some embodiments, L¹ is —CH₂— and L² is —CH₂—.Particular examples of compounds according to these embodiments includethose where M-L is M-CH₂—NH—CH₂— or

In still other embodiments, M-L is M-S-L¹-NR⁴-L², wherein L¹ is C₁₋₆alkyl, and L² is C₁₋₆ alkyl. In particular compounds according to theseembodiments, M-L is M-S—CH₂CH₂—NH—CH₂—.

In particular embodiments, M is selected from the group consisting of:

-   -   a) phenyl, b) pyridyl, c) pyrazinyl, d) pyrimidinyl, e)        pyridazinyl, f) oxiranyl, g) aziridinyl, h) furanyl, i)        thiophenyl, j) pyrrolyl, k) oxazolyl, l) isoxazolyl, m)        imidazolyl, n) pyrazolyl, o) isothiazolyl, p) thiazolyl, q)        triazolyl, r) tetrazolyl, s) indolyl, t) purinyl, u)        benzofuranyl, v) benzoxazolyl, w) benzisoxazolyl, x)        quinolinyl, y) isoquinolinyl, z) quinoxalinyl, aa) quinazolinyl,        bb) cinnolinyl, cc) cyclopropyl, dd) cyclobutyl, ee)        cyclopentyl, ff) cyclohexyl, gg) cycloheptyl, hh) oxetanyl, ii)        tetrahydrofuranyl, jj) tetrahydropyranyl, kk) azetidinyl, ll)        pyrrolidinyl, mm) piperidinyl, nn) thietanyl, oo)        tetrahydrothiophenyl, pp) tetrahydrothiopyranyl, qq)        piperazinyl, rr) quinuclidinyl, ss)        1-azabicyclo[2.2.1]hyeptanyl, tt) morpholinyl, uu)        thiomorpholinyl, vv) thiooxomorpholinyl, ww)        thiodioxomorpholinyl, and xx) benzothiophenyl        wherein any of a)-xx) optionally is substituted with one or more        R⁵ groups. In particular embodiments, M is 4-isoxazolyl,        [1,2,3]triazol-1-yl, 3H-[1,2,3]triazol-4-yl, 1H-tetrazol-5-yl,        piperidin-1-yl, or pyrrolidin-1-yl.

In preferred embodiments, A is phenyl, substituted phenyl, pyridyl, orsubstituted pyridyl. Under certain circumstances, when A is pyridin-4-ylsubstituted with M-L at the 2 position, M-L is not (imidazol-1-yl)methylor (morpholin-4-yl)methyl.

In preferred embodiments, B is phenyl or substituted phenyl. Morepreferably, B is substituted phenyl. Preferred substituents includehalogens, and in particular, fluorine.

Under certain circumstances, when B is unsubstituted phenyl, M-L isselected from the group consisting of M-X, M-L¹-X, M-L¹-X-L²,M-X-L¹-X-L², M-X—X—, M-L¹-X—X—, M-X—X-L², and M-L¹-X—X-L². Under certaincircumstances, when B is pyridin-2-yl substituted with A at the 5position, M-L is selected from the group consisting of M-X, M-L¹-X,M-L¹-X-L², M-L¹-X-L²-X, M-X—X—, M-X—X-L², and M-L¹-X—X-L².

In another aspect, the invention provides a pharmaceutical compositioncomprising an effective amount of one or more of the foregoing compoundsand a pharmaceutically acceptable carrier. Suitable formulating agentsare described in detail in section 5 hereinbelow.

One or more of the foregoing compounds may also be incorporated into amedical device. For example, a medical device, such as a medical stent,can contain or be coated with one or more of the compounds of theinvention.

In another aspect, the invention provides a method for treating amicrobial infection, a fungal infection, a viral infection, a parasiticdisease, a proliferative disease, an inflammatory disease, or agastrointestinal motility disorder in a mammal. The method involvesadministering an effective amount of one or more compounds orpharmaceutical compositions of the invention, for example, via oral,parenteral or topical routes.

The invention provides a method of treating a disorder in a mammalcomprising the step of administering to the mammal an effective amountof one or more compounds of the invention thereby to ameliorate asymptom of a particular disorder. Such a disorder can be selected fromthe group consisting of a skin infection, nosocomial pneumonia,post-viral pneumonia, an abdominal infection, a urinary tract infection,bacteremia, septicemia, endocarditis, an atrio-ventricular shuntinfection, a vascular access infection, meningitis, surgicalprophylaxis, a peritoneal infection, a bone infection, a jointinfection, a methicillin-resistant Staphylococcus aureus infection, avancomycin-resistant Enterococci infection, a linezolid-resistantorganism infection, and tuberculosis.

3. Synthesis of the Compounds of the Invention

The invention provides methods and intermediates for making compounds ofthe present invention. The following schemes depict some exemplarychemistries available for synthesizing the compounds of the invention.It will be appreciated, however, that the desired compounds may besynthesized using other alternative chemistries known in the art.

The following examples illustrate some of the compounds of the presentinvention. Compounds of general structures Ia through IVb (wherein X isCH or N) can be synthesized by the chemistries exemplified below in thefollowing schemes.

Scheme A exemplifies the synthesis of biaryl amine intermediate 5, whichis useful in producing certain compounds of the present invention. Knowniodoaryl oxazolidinone intermediate 1 (see U.S. Pat. Nos. 5,523,403 and5,565,571) is coupled to a substituted aryl boronic acid (the Suzukireaction) to produce biaryl alcohol 2. Other coupling reactions (forexample, the Stille reaction) using alternate coupling intermediateseasily obtained or synthesized by those skilled in the art could also beemployed to synthesize target biaryl intermediates similar to 2. Thesealternate coupling reactions are within the scope of the presentinvention. Alcohol 2 is then converted to amine 5 by chemistry wellknown to those skilled in the art.

Scheme B illustrates the synthesis of intermediates 7 and 8 of thepresent invention using Suzuki coupling chemistry between boronic acidsand aryl triflates. Boronic ester 6 is treated with an appropriate aryltriflate to yield the BOC-protected biaryl 7. The BOC group of 7 isremoved to provide amine 8, an intermediate useful in the synthesis ofcertain compounds of the present invention.

Scheme C depicts the synthesis of intermediates 9-13, which are usefulin producing certain methoxy-substituted biaryl derivatives of thepresent invention. Suzuki coupling of boronic ester 6 produces biarylaldehyde 9, which can be reduced to alcohol 10. Mesylation of 10 yields11 that can be converted to azide 12. Reduction of azide 12 yields amine13.

Scheme D depicts the synthesis of pyridyl intermediates, which areuseful for the synthesis of compounds of the present invention, viasimilar chemistry to that shown in Scheme C. Coupling of boronic ester 6to a halopyridine aldehyde produces biaryl aldehyde 14. Aldehyde 14serves as the precursor to intermediates 15-18 via chemistry describedabove.

Biaryl aldehyde 19 (Scheme E) can be synthesized from a Suzuki couplingof iodide 1 and 4-formylphenylboronic acid. Scheme E illustrates howintermediate aldehydes of type 19, 9, and 14 can be converted viareductive amination chemistry to other amines, such as amines 20-22,which are useful as intermediates for the synthesis of certain compoundsof the invention.

Scheme F depicts the general synthesis of compounds of type Ia and Ibfrom amines of type 5, 13, 18, and 20-22. Compounds of type Ia and Ibare synthesized via acylation of amines 5, 13 and 18 and 20-22 with theappropriate acids using, for example,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) asthe coupling agent. Compounds 4001-4007 were specifically synthesizedfrom amine 5 and the appropriate carboxylic acids.

Scheme G highlights the synthesis of compounds of general structure IIfrom amines of type 5 and 18. The amine can be acylated with carboxylicacids using EDCI (or other commonly employed peptide coupling reagentsknown in the art) to afford amides II. Acid chlorides can be purchasedor synthesized and allowed to react with amines 5 and 18, in thepresence of bases such as triethylamine, to also produce amides II.Alternatively, carboxylic acids can be pre-loaded onto a solid polymericsupport, such as a tetrafluorophenol containing resin (TFP resin), andreacted with amines to yield amide products of general structure II(such as compounds 4008-4015).

Scheme H illustrates the synthesis of compounds of general structureIIIa from amines of type 5, 13, and 18 using reductive aminationchemistry. For example, biaryl amine compounds 4016-4028 are synthesizedin this manner.

Scheme I depicts the synthesis of general structure IIIb of the presentinvention from amine intermediate 8. For example, compounds 4029-4031are synthesized using this reductive amination chemistry.

Scheme J shows the synthesis of compounds of general structure IVa andIVb. Amines 20, 21, and 22 can be converted to tertiary amines IVa, suchas compounds 4032-4034 and 4036, using standard reductive aminationchemistry employed earlier for other derivatives. This reductiveamination chemistry can be employed on biaryl aldehyde intermediatessuch as 19, 9, and 14 to yield optionally substituted amines of generalstructure IVb, illustrated by compound 4037.

It should be noted that, when X is N, any of the synthetic routesdescribed above may be used to produce compounds having any regioisomerof pyridine (e.g., pyridin-2-yl or pyridin-3-yl).

In addition, the invention provides alternative approaches forsynthesizing compounds of the invention. In one approach, the methodincludes the step of combining a compound of formula (I):

with a compound of formula (II):

in a solvent in the presence of a base and a palladium catalyst, wherein

Q is a boronate having the formula —BY₂, wherein

-   -   Y, at each occurrence, independently is selected from the group        consisting of:        -   a) —OH, and b) —O—C₁₋₄ alkyl,    -   alternatively, two Y groups taken together are selected from the        group consisting of:        -   a) —OC(R⁴)(R⁴)C(R⁴)(R⁴)O—, and b) —OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—,            alternatively, two Y groups taken together with the boron to            which they are bound comprise a BF₃ alkali metal salt;

Z is selected from the group consisting of:

-   -   a) I, b) Br, c) Cl, and d) R⁴OSO₃—; and    -   A, B, Het, L, M, R¹, R², R³, R⁴, m, and n are defined as        described above.

In another approach, the method includes the step of combining acompound of formula (III):

with a compound of formula (IV):

in a solvent in the presence of a base and a palladium catalyst, whereinA, B, Het, L, M, R¹, R², R³, R⁴, Q, Z, m, and n are defined as describedabove.

In either approach, Z can be I. Furthermore, Q can be —BF₂.KF or

In some embodiments, the base is selected from the group consisting ofan alkali metal hydroxide, an alkali metal carbonate, an alkali metalfluoride, a trialkyl amine, and mixtures thereof. Examples of suitablebases include potassium carbonate, sodium carbonate, potassium fluoride,triethylamine, diisopropylethylamine, and mixtures thereof. Inparticular embodiments, the ratio of equivalents of base to equivalentsof compound (I) or compound (III) is about 3:1.

In some embodiments, the palladium catalyst is a ligand coordinatedpalladium (0) catalyst, such as a tetrakis(trialkylphosphine)palladium(0) or a tetrakis(triarylphosphine)palladium (0) catalyst. An example ofa suitable palladium catalyst is tetrakis(triphenylphosphine)palladium(0). In particular embodiments, the ratio of the equivalents oftetrakis(triphenylphosphine)palladium (0) to the equivalents of compound(I) or compound (III) is about 1:20.

In some embodiments, the solvent comprises an aqueous solvent. In otherembodiments, the solvent comprises a mixture of water and an organicsolvent, wherein the organic solvent is selected from the groupconsisting of methanol, ethanol, propanol, isopropanol, butanol,isobutanol, secondary butanol, tertiary butanol, benzene, toluene,tetrahydrofuran, dimethylformamide, 1,2-diethyl ether, dimethoxyethane,diisopropyl ether, methyltertiarybutyl ether, methoxymethyl ether,2-methoxyethyl ether, 1,4-dioxane, 1,3-dioxolane, and mixtures thereof.In a particular embodiment, the solvent is a mixture of water, toluene,and ethanol in a ratio, for example, of about 1:3:1 by volume.

In some embodiments, the method is carried out at a temperature betweenabout 20° C. and about 100° C. In other embodiments, the process iscarried out at the reflux temperature of the solvent.

4. Characterization of Compounds of the Invention

Compounds designed, selected and/or optimized by methods describedabove, once produced, may be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules may becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening may be used to speed up analysisusing such assays. As a result, it may be possible to rapidly screen themolecules described herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it may be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin, High Throughput Screening, (MarcelDekker, 1998); and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies.

A variety of binding assays may be useful in screening new molecules fortheir binding activity. One approach includes surface plasmon resonance(SPR) that can be used to evaluate the binding properties of moleculesof interest with respect to a ribosome, ribosomal subunit or a fragmentthereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor™ fromPharmacia Biosensor, Piscatawy, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization.

Fluorescence polarization (FP) is a measurement technique that canreadily be applied to protein-protein, protein-ligand, or RNA-ligandinteractions in order to derive IC₅₀s and Kds of the associationreaction between two molecules. In this technique one of the moleculesof interest is conjugated with a fluorophore. This is generally thesmaller molecule in the system (in this case, the compound of interest).The sample mixture, containing both the ligand-probe conjugate and theribosome, ribosomal subunit or fragment thereof, is excited withvertically polarized light. Light is absorbed by the probe fluorophores,and re-emitted a short time later. The degree of polarization of theemitted light is measured. Polarization of the emitted light isdependent on several factors, but most importantly on viscosity of thesolution and on the apparent molecular weight of the fluorophore. Withproper controls, changes in the degree of polarization of the emittedlight depends only on changes in the apparent molecular weight of thefluorophore, which in-turn depends on whether the probe-ligand conjugateis free in solution, or is bound to a receptor. Binding assays based onFP have a number of important advantages, including the measurement ofIC₅₀s and Kds under true homogenous equilibrium conditions, speed ofanalysis and amenity to automation, and ability to screen in cloudysuspensions and colored solutions.

(3) Protein Synthesis.

It is contemplated that, in addition to characterization by theforegoing biochemical assays, the compound of interest may also becharacterized as a modulator (for example, an inhibitor of proteinsynthesis) of the functional activity of the ribosome or ribosomalsubunit.

Furthermore, more specific protein synthesis inhibition assays may beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is a inhibitor of protein synthesis.

Furthermore, the compounds may be assayed for anti-proliferative oranti-infective properties on a cellular level. For example, where thetarget organism is a microorganism, the activity of compounds ofinterest may be assayed by growing the microorganisms of interest inmedia either containing or lacking the compound. Growth inhibition maybe indicative that the molecule may be acting as a protein synthesisinhibitor. More specifically, the activity of the compounds of interestagainst bacterial pathogens may be demonstrated by the ability of thecompound to inhibit growth of defined strains of human pathogens. Forthis purpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms. The assays may be performed inmicrotiter trays according to conventional methodologies as published byThe National Committee for Clinical Laboratory Standards (NCCLS)guidelines (NCCLS. M7-A5-Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN1-56238-394-9)).

5. Formulation and Administration

The compounds of the invention may be useful in the prevention ortreatment of a variety of human or other animal disorders, including forexample, bacterial infection, fungal infections, viral infections,parasitic diseases, and cancer. It is contemplated that, onceidentified, the active molecules of the invention may be incorporatedinto any suitable carrier prior to use. The dose of active molecule,mode of administration and use of suitable carrier will depend upon theintended recipient and target organism. The formulations, both forveterinary and for human medical use, of compounds according to thepresent invention typically include such compounds in association with apharmaceutically acceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith the other ingredients of the formulations and not deleterious tothe recipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,anti-bacterial and anti-fungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances isknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds (identified or designedaccording to the invention and/or known in the art) also can beincorporated into the compositions. The formulations may conveniently bepresented in dosage unit form and may be prepared by any of the methodswell known in the art of pharmacy/microbiology. In general, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to becompatible with its intended route of administration. Examples of routesof administration include oral or parenteral, for example, intravenous,intradermal, inhalation, transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Useful solutions for oral or parenteral administration can be preparedby any of the methods well known in the pharmaceutical art, described,for example, in Remington's Pharmaceutical Sciences, 18th ed. (MackPublishing Company, 1990). Formulations for parenteral administrationcan also include glycocholate for buccal administration,methoxysalicylate for rectal administration, or citric acid for vaginaladministration. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.Suppositories for rectal administration also can be prepared by mixingthe drug with a non-irritating excipient such as cocoa butter, otherglycerides, or other compositions which are solid at room temperatureand liquid at body temperatures. Formulations also can include, forexample, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, and hydrogenated naphthalenes. Formulations for directadministration can include glycerol and other compositions of highviscosity. Other potentially useful parenteral carriers for these drugsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes. Formulations for inhalationadministration can contain as excipients, for example, lactose, or canbe aqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administrationmay be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug may alsobe administered in the form of a bolus, electuary or paste. A tablet maybe made by compressing or molding the drug optionally with one or moreaccessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyetheylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as manitol, sorbitol,sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration may be in theform of a sterile aqueous preparation of the drug that may be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems may also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Particularly usefulare carriers capable of forming a film or layer over the skin tolocalize application and inhibit removal. For topical administration tointernal tissue surfaces, the agent can be dispersed in a liquid tissueadhesive or other substance known to enhance adsorption to a tissuesurface. For example, hydroxypropylcellulose or fibrinogen/thrombinsolutions can be used to advantage. Alternatively, tissue-coatingsolutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect may beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants generally are known in the art, and include, forexample, for transmucosal administration, detergents and bile salts.Transmucosal administration can be accomplished through the use of nasalsprays or suppositories. For transdermal administration, the activecompounds typically are formulated into ointments, salves, gels, orcreams as generally known in the art.

The active compounds may be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. Liposomalsuspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals. Furthermore, administration can be by periodicinjections of a bolus, or can be made more continuous by intravenous,intramuscular or intraperitoneal administration from an externalreservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in effective amounts, e.g., amounts that provideappropriate concentrations of the drug to target tissue for a timesufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations described herein and/or known in the art.Where the drug comprises part of a tissue or organ preservationsolution, any commercially available preservation solution can be usedto advantage. For example, useful solutions known in the art includeCollins solution, Wisconsin solution, Belzer solution, Eurocollinssolution and lactated Ringer's solution.

Active compound as identified or designed by the methods describedherein can be administered to individuals to treat disorders(prophylactically or therapeutically). In conjunction with suchtreatment, pharmacogenomics (i.e., the study of the relationship betweenan individual's genotype and that individual's response to a foreigncompound or drug) may be considered. Differences in metabolism oftherapeutics can lead to severe toxicity or therapeutic failure byaltering the relation between dose and blood concentration of thepharmacologically active drug. Thus, a physician or clinician mayconsider applying knowledge obtained in relevant pharmacogenomicsstudies in determining whether to administer a drug as well as tailoringthe dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections inmammals, the compounds or pharmaceutical compositions thereof will beadministered orally, parenterally and/or topically at a dosage to obtainand maintain a concentration, that is, an amount, or blood-level ortissue level of active component in the animal undergoing treatmentwhich will be anti-microbially effective. The term “effective amount” isunderstood to mean that the compound of the invention is present in oron the recipient in an amount sufficient to elicit biological activity,for example, anti-microbial activity, anti-fungal activity, anti-viralactivity, anti-parasitic activity, and/or anti-proliferative activity.Generally, an effective amount of dosage of active component will be inthe range of from about 0.1 to about 100, more preferably from about 1.0to about 50 mg/kg of body weight/day. The amount administered will alsolikely depend on such variables as the type and extent of disease orindication to be treated, the overall health status of the particularpatient, the relative biological efficacy of the compound delivered, theformulation of the drug, the presence and types of excipients in theformulation, and the route of administration. Also, it is to beunderstood that the initial dosage administered may be increased beyondthe above upper level in order to rapidly achieve the desiredblood-level or tissue level, or the initial dosage may be smaller thanthe optimum and the daily dosage may be progressively increased duringthe course of treatment depending on the particular situation. Ifdesired, the daily dose may also be divided into multiple doses foradministration, for example, two to four times per day.

6. Examples

Exemplary compounds synthesized in accordance with the invention arelisted in Table 2.

TABLE 2 Compound Number Structure 1001

N-{3-[2-Fluoro-4′-(2-[1,2,3]triazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1002

N-{3-[2-Fluoro-4′-(2-imidazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1003

2-(4-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-piperazin-1-yl)-acetamide 1004

N-{3-[4′-(4-Cyanomethyl-piperazin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1005

N-{3-[4′-(4-Cyanomethyl-piperazin-1-ylmethyl)-2,3′-difluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1006

N-{3-[2-Fluoro-4′-(4-formyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1007

N-{3-[2-Fluoro-4′-(1H-tetrazol-5-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1008

N-[3-(2-Fluoro-4′-imidazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1009

N-[3-(2,3′-Difluoro-4′-[1,2,3]triazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1010

N-[3-(2,3′-Difluoro-4′-imidazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1011

N-{3-[4′-(4-Aminomethyl-[1,2,3]triazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1012

N-{3-[2-Fluoro-4′-(4-methylaminomethyl-[1,2,3]triazol-1-ylmethy)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1013

N-{3-[4′-(4-Dimethylaminomethyl-[1,2,3]triazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1014

N-(1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-1H-[1,2,3]triazol-4-ylmethyl)-2-amino-acetamide1015

N-[3-(2-Fluoro-4′-[1,2,3]triazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1016

N-{3-[2-Fluoro-4′-(5-(S)-oxo-2,5-(S)-dihydro-[1,2,4]oxadiazol-3-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1017

N-{3-[2-Fluoro-4′-(5-(S)-methyl-[1,2,4]oxadiazol-3-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1018

N-{3-[2,6-Difluoro-4′-(4-hydroxymethyl-[1,2,3]triazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1019

N-{3-[4′-(4-Dimethylaminomethyl-[1,2,3]triazol-1-ylmethyl)-2,6-difluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1020

N-[3-(2-Fluoro-4′-{2-[(tetrahydro-furan-2-ylmethyl)-amino]-thiazol-4-ylmethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1021

N-(3-{2-Fluoro-4′-[2-(3-methoxy-benzylamino)-thiazol-4-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1022

N-{3-[4′-(3-Cyano-azetidin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1023

N-[3-(2-Fluoro-4-[1,2,3]triazol-2-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1024

N-{3-[4′-(5-Amino-tetrazol-2-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1025

N-{3-[4′-(5-Amino-tetrazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1026

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-5-amino-1H-[1,2,3]triazole-4-carboxylic acid amide1027

N-{3-[2-Fluoro-4′-(7-oxo-6,7-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}- acetamide1028

N-{3-[2-Fluoro-4′-(4-hydroxymethyl-[1,2,3]triazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1029

N-(3-{2-Fluoro-4′-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1030

N-(3-{2-Fluoro-4′-[4-(2-hydroxy-ethyl)-piperidin-1-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1031

N-{3-[4′-(R)-(1-Amino-2-imidazol-1-yl-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1032

5-(S)-Aminomethyl-3-(2-fluoro-4′-tetrazol-1-ylmethyl-biphenyl-4-yl)-oxazolidin-2-one 1033

2-Chloro-N-[3-(2-fluoro-4′-tetrazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1034

2,2-Dichloro-N-[3-(2-fluoro-4′-tetrazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1035

N-{3-[3-Fluoro-4-(6-tetrazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1036

N-{3-[3-Fluoro-4-(6-[1,2,3]triazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1037

N-[3-(2-Fluoro-4′-[1,2,4]triazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1038

N-(3-{4′-[4-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-ylmethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1039

[{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-(2H-tetrazol-5-(R/S)-yl)-methyl]-carbamic acid benzylester 1040

N-(3-{4′-[Amino-(2H-tetrazol-5-(R/S)-yl)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1041

[{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-(2-methyl-2H-tetrazol-5-(R/S)-yl)-methyl]-carbamic acidbenzyl ester 1042

N-(3-{4′-[Amino-(2-methyl-2H-tetrazol-5-(R/S)-yl)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1043

N-[3-(2-Fluoro-4′-pyrazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1044

N-(3-{2-Fluoro-4′-[2-(4-formyl-piperazin-1-yl)-1-(S)-hydroxy-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1045

N-(3-{2-Fluoro-4′-[1-(R)-(4-formyl-piperazin-1-yl)-2-hydroxy-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1046

N-{3-[2-Fluoro-4′-(1-(S)-hydroxy-2-imidazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1047

N-[3-(2-Fluoro-4′-tetrazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1048

N-[3-(2,6-Difluoro-4′-tetrazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1049

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-1H-pyrazole-4-carboxylic acid ethyl ester 1050

N-{3-[2-Fluoro-4′-(4-hydroxymethyl-imidazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1051

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-1H-pyrazole-4-carboxylic acid 1052

N-{3-[2-Fluoro-4′-(4-methyl-pyrazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1053

N-{3-[4′-(3-Amino-pyrazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1054

N-[3-(2-Fluoro-4′-pyrrol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1055

N-{3-[2-Fluoro-4′-(3-formyl-pyrrol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1056

N-[3-(2-Fluoro-4′-tetrazol-2-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1057

3-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-5-amino-3H-imidazole-4-carboxylic acid amide 1058

N-{3-[2-Fluoro-4′-(5-methyl-tetrazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1059

N-{3-[2-Fluoro-4′-(5-methyl-tetrazol-2-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1060

N-(3-{2-Fluoro-4′-[1-(R)-hydroxy-2-(1H-tetrazol-5-yl)-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1061

N-{3-[2-Fluoro-4′-(1-(S)-hydroxy-2-[1,2,3]triazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1062

N-{3-[4′-(2-Azetidin-1-yl-1-(S)-hydroxy-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1063

N-{3-[4′-[1-(R)-Azetidin-1-yl-2-hydroxy-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1064

N-[3-(2-Fluoro-4′-thiomorpholin-4-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1065

N-{3-[2-Fluoro-4′-(1-oxo-1lambda*4*-thiomorpholin-4-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1066

N-{3-[2-Fluoro-4′-(2-methyl-imidazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1067

N-{3-[2-Fluoro-4′-(5-methyl-imidazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1068

N-{3-[4′-(2,4-Dimethyl-imidazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1069

N-{3-[4′-(3-Amino-[1,2,4]triazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1070

N-[3-(2-Fluoro-4′-thiazolidin-3-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1071

N-{3-[3-Fluoro-4-(6-pyrrol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1072

N-{3-[3-Fluoro-4-(6-[1,2,4]triazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1073

N-{3-[2-Fluoro-4′-(2-hydroxy-1-(R)-[1,2,3]triazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1074

N-(3-{4′-[1-(R)-(3,3-Difluoro-piperidin-1-yl)-2-hydroxy-ethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1075

N-(3-{4′-[2-(3,3-Difluoro-piperidin-1-yl)-1-(S)-hydroxy-ethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1076

N-{3-[3-Fluoro-4-(6-pyrazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1077

N-{3-[3-Fluoro-4-(6-imidazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1078

N-{3-[2-Fluoro-4′-(2-methylsulfanyl-4,5-dihydro-imidazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1079

N-{3-[2-Fluoro-4′-(5-methylsulfanyl-tetrazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1080

N-{3-[2-Fluoro-4′-(5-methylsulfanyl-tetrazol-2-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1081

N-{3-[4′-(5-Ethylsulfanyl-tetrazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1082

N-{3-[4′-(5-Ethylsulfanyl-tetrazol-2-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1083

N-{3-[4′-(5-Chloro-tetrazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1084

3-(2-Fluoro-4′-imidazol-1-ylmethyl-biphenyl-4-yl)-5-(R)-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 1085

3-(2-Fluoro-4′-pyrazol-1-ylmethyl-biphenyl-4-yl)-5-(R)-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 1086

N-{3-[2-Fluoro-4′-(1H-imidazol-4-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1087

N-{3-[2-Fluoro-4′-(3-(S)-hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1088

N-{3-[2-Fluoro-4′-(3-(R)-hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1089

N-{3-[2,6-Difluoro-4′-(4-hydroxymethyl-[1,2,3]triazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1090

N-[3-(4′-Azetidin-1-ylmethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1091

N-{3-[4′-(3-(R)-Amino-pyrrolidin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1092

N-{3-[4′-(3-(S)-Amino-pyrrolidin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1093

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-pyrrolidine-3-(R/S)-carboxylic acid amide 1094

N-{3-[2-Fluoro-4′-(4-fluoro-piperidin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1095

N-{3-[2-Fluoro-4′-(5-fluoromethyl-2-oxo-oxazolidin-3-(R/S)ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1096

N-{3-[2-Fluoro-4′-(3-(R/S)-fluoro-piperidin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1097

N-{3-[4′-(3,3-Difluoro-piperidin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1098

N-(3-{2-Fluoro-4′-[6-(3-fluoro-propylamino)-purin-9-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1099

N-(3-{2-Fluoro-4′-[6-(2-hydroxy-ethylamino)-purin-9-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1100

N-{3-[4′-(6-Chloro-purin-9-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1101

N-{3-[2-Fluoro-4′-(2-oxo-oxazolidin-3-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1102

N-(3-{2-Fluoro-4′-[6-(2-fluoro-ethylamino)-purin-9-ylmethyl]-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1103

N-(3-{4′-[6-(2,2-Difluoro-ethylamino)-purin-9-ylmethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1104

N-(3-{2-Fluoro-4′-[6-(2,2,2-trifluoro-ethylamino)-purin-9-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1105

N-{3-[4′-(6-Dimethylamino-purin-9-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1106

N-{3-[2-Fluoro-4′-(6-methylamino-purin-9-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1107

N-(3-{2-Fluoro-4′-[6-(3-hydroxy-propylamino)-purin-9-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1108

N-(3-{2-Fluoro-4′-[6-(2-methylsulfanyl-ethylamino)-purin-9-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1109

N-(3-{2-Fluoro-4′-[6-(4-hydroxy-butylamino)-purin-9-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 1110

N-{3-[4′-(6-Amino-purin-9-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1111

N-{3-[2-Fluoro-4′-(6-oxo-1,6-dihydro-purin-9-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1112

N-[3-(2-Fluoro-4′-isoxazolidin-2-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1113

N-{3-[4′-(2-Amino-imidazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1114

N-{3-[2-Fluoro-4′-(7-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-c]pyrimidin-6-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1115

N-[3-(2-Fluoro-4′-pyrrolidin-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1116

N-[3-(2-Fluoro-4′-piperidin-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 1117

N-{3-[2-Fluoro-4′-(1-(S)-hydroxy-2-morpholin-4-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1118

N-{3-[2-Fluoro-4′-(2-hydroxy-1-(R)-morpholin-4-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1119

(1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-pyrrolidin-3-(R)-yl)-carbamic acid tert-butyl ester1120

(1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester1121

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-piperidine-3-(R/S)-carboxylic acid amide 1122

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-pyrrolidine-2-(S)-carboxylic acid amide 1123

N-{3-[2-Fluoro-4′-(3-oxo-piperazin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1124

N-{3-[4′-(2,2-Dimethyl-4-oxo-imidazolidin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1125

1-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-azetidine-3-(R/S)-carboxylic acid amide 1126

1-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-azetidine-2-carboxylic acid amide 1127

N-{3-[2-Fluoro-4′-(2-oxo-piperazin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1128

2-(4-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-oxo-piperazin-1-yl)-acetamide 1129

N-{3-[4′-(4-Cyanomethyl-2-oxo-piperazin-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 1130

N-{3-[2-Fluoro-4′-(2-oxo-4-[1,2,3]thiadiazol-4-ylmethyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2001

N-{3-[2-Fluoro-4′-(5-methyl-isoxazol-3-yloxymethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2002

N-{3-[2-Fluoro-4′-([1,2,4]triazol-4-ylaminomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2003

N-(3-{2-Fluoro-4′-[(3-methyl-isoxazol-5-ylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2004

N-(3-{2-Fluoro-4′-[(5-methyl-isoxazol-3-ylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2005

4-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-piperidine-1-carboxylic acid ethyl ester2006

N-(3-{4′-[(1-Aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2007

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-benzamide 2008

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-thiophene-3-carboxylic acid amide 2009

N-(3-{2-Fluoro-4′-[(3-oxo-isoxazolidin-4-(R)-ylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2010

N-(3-{2-Fluoro-4′-[(3-oxo-isoxazolidin-4-(S)-ylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2011

N-{3-[4′-(Azetidin-3-(R/S)-ylaminomethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2012

N-(3-{4′-[(3-Aminomethyl-[1,2,4]thiadiazol-5-ylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2013

N-[5-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-[1,2,4]thiadiazol-3-ylmethyl]-2-(S)-amino-propionamide 2014

2,6-Diamino-hexanoic acid[5-({4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-[1,2,4]thiadiazol-3-ylmethyl]-amide 2015

N-{3-[2-Fluoro-4′-(1-methyl-1H-tetrazol-5-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2016

N-{3-[2-Fluoro-4′-(3H-[1,2,3]triazol-4-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2017

N-{3-[4′-(4,6-Dioxo-1,4,5,6-tetrahydro-pyrimidin-2-ylsulfanylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2018

N-{3-[2-Fluoro-4′-(pyridin-2-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2019

N-{3-[2-Fluoro-4′-(pyridin-4-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2020

N-{3-[2-Fluoro-4′-(1-methyl-1H-tetrazole-5-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2021

N-{3-[2-Fluoro-4′-(3H-[1,2,3]triazole-4-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2022

N-{3-[2-Fluoro-4′-(pyridine-4-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2023

N-{3-[2-Fluoro-4′-(pyridine-2-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2024

N-{3-[2-Fluoro-4′-(1-methyl-1H-tetrazole-5-sulfonylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2025

N-{3-[2-Fluoro-4′-(3H-[1,2,3]triazole-4-sulfonylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2026

N-(3-{2-Fluoro-4′-[2-(3H-[1,2,3]triazol-4-ylsulfanyl)-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2027

N-(3-{4′-[1-(2-Dimethylamino-ethyl)-1H-tetrazol-5-ylsulfanylmethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2028

N-{3-[4′-(5-Amino-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2029

N-{3-[2-Fluoro-4′-([1,3,4]thiadiazol-2-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2030

N-{3-[2-Fluoro-4′-(thiazol-2-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2031

N-{3-[2-Fluoro-4′-(4-methyl-thiazol-2-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2032

N-{3-[2-Fluoro-4′-(1H-imidazol-2-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2033

N-{3-[2-Fluoro-4′-(2-methyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2034

N-{3-[2-Fluoro-4′-(2-methyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2035

N-{3-[2-Fluoro-4′-([1,3,4]thiadiazole-2-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2036

N-{3-[2-Fluoro-4′-(thiazole-2-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2037

N-{3-[2-Fluoro-4′-(4-methyl-thiazole-2-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2038

N-{3-[2-Fluoro-4′-(1H-imidazole-2-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2039

N-{3-[2-Fluoro-4′-(2-methyl-2H-[1,2,4]triazole-3-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2040

N-(3-{3-Fluoro-4-[6-(3H-[1,2,3]triazol-4-ylsulfanylmethyl)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2041

N-{3-[2-Fluoro-4′-(pyridin-2-yl-hydrazonomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2042

N-(3-{2-Fluoro-4′-[(4-trifluoromethyl-pyrimidin-2-yl)-hydrazonomethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2043

N-(3-{2-Fluoro-4′-[(1-methyl-1H-imidazole-4-sulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2044

N-(3-{2-Fluoro-4′-[(6-morpholin-4-yl-pyridine-3-sulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2045

N-{3-[2-Fluoro-4′-(pyridin-3-ylsulfamoylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2046

N-{3-[2-Fluoro-4′-([1,2,4]triazol-4-ylaminomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2047

N-{3-[2-Fluoro-4′-(2H-[1,2,4]triazol-3-ylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2048

N-{3-[2-Fluoro-4′-(N′-pyridin-2-yl-hydrazinomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2049

N-(3-{4′-[N′-(4,5-Dihydro-1H-imidazol-2-yl)-hydrazinomethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2050

N-{3-[2-Fluoro-4′-(isoxazol-3-ylaminomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2051

N-(3-{2-Fluoro-4′-[(quinoline-8-sulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2052

N-(3-{2-Fluoro-4′-[(1-methyl-1H-imidazole-4-sulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2053

N-(3-{2-Fluoro-4′-[(6-morpholin-4-yl-pyridine-3-sulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2054

N-{3-[2-Fluoro-4 ′-pyridin-3-ylsulfamoylmethyl)-biphenyl-4-yl]2-oxo-oxazolidin-5-(S)-ylmethyl}acetamide 2055

5-({4′[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-3H-imidazole-4-carboxylic acid amide 2056

N-{3-[2-Fluoro-4′-(morpholin-4-yliminomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 2057

N-(3-{2-Fluoro-4′-[(4-methyl-piperazin-1-ylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2058

N-(3-{2-Fluoro-4′-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 2059

N-(3-{2-Fluoro-4′-[(2-oxo-piperidin-3-(S)-ylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 3001

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethylsulfanyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 3002

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethanesulfinyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 3003

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethanesulfonyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 3004

N-{3-[2-Fluoro-4′-(1-oxy-pyridin-4-ylmethanesulfonyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 3005

N-(3-{2-Fluoro-4′-[(pyridin-4-ylmethyl)-sulfamoyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 3006

N-(3-{2-Fluoro-4′-[(pyridin-2-ylmethyl)-sulfamoyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 3007

N-{3-[2-Fluoro-4′-(2-pyridin-2-yl-ethylsulfamoyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4001

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acrylamide 4002

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-pyridin-3-yl-acrylamide 4003

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(2,4-dimethoxy-6-methyl-pyrimidin-5-yl)-acrylamide 4004

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(4-hydroxy-2-methoxy-6-methyl-pyrimidin-5-yl)-acrylamide 4005

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acrylamide 4006

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-pyrimidin-5-yl-acrylamide 4007

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(1-methyl-6-oxo-1,6-dihydro-pyrimidin-5-yl)-acrylamide 4008

Quinoline-4-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4009

Quinoline-3-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4010

1-Methyl-1H-pyrrole-2-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4011

1H-Indole-6-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4012

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-methanesulfonyl-benzamide 4013

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-4-fluoro-benzamide 4014

Benzo[1,3]dioxole-5-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4015

5-Methoxy-1H-indole-2-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4016

N-[3-(2-Fluoro-4′-{[(quinolin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}- acetamide 4017

N-(3-{2-Fluoro-4′-[(4-pyridin-2-yl-benzylamino)-methyl}-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4018

N-[3-(2-Fluoro-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4019

N-[3-(2-Fluoro-4′-{[(quinolin-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4020

N-[3-(4′-{[(Benzofuran-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4021

N-[3-(2-Fluoro-4′-{[(quinolin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4022

N-[3-(2-Fluoro-4′-{[(naphthalen-1-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4023

N-[3-(2-Fluoro-4′-{[(furan-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4024

N-[3-(2-Fluoro-4′-{[(pyridin-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4025

N-[3-(2-Fluoro-4′-{[(pyridin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4026

N-{3-(2-Fluoro-4′-{[(furan-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4027

N-[3-(2-Fluoro-2′-methoxy-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4028

N-[3-(2-Fluoro-4′-{[(furan-3-ylmethyl)-amino]-methyl}-2′-methoxy-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4029

N-[3-(2-Fluoro-4′-{2-hydroxy-1-(R)-[(pyridin-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4030

N-[3-(4′-{1-(R)-[(2,4-Dihydroxy-6-methyl-pyrimidin-5-ylmethyl)-amino]-2-hydroxy-ethyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4031

N-[3-(2-Fluoro-4′-{2-hydroxy-1-(R)-[(quinolin-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4032

N-(3-{2-Fluoro-4′-[(methyl-quinolin-4-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)- acetamide 4033

N-(3-{2-Fluoro-2′-methoxy-4′-[(methyl-pyridin-4-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4034

N-(3-{2-Fluoro-4′-[(furan-3-ylmethyl-methyl-amino)-methyl]-2′-methoxy-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4035

N-(3-{4′-[(Ethyl-pyridin-4-ylmethyl-amino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4036

N-[3-(4′-{[(2,4-Dihydroxy-6-methyl-pyrimidin-5-ylmethyl)-methyl-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4037

N-[3-(4′-{[Bis-(4-hydroxy-3-methoxy-benzyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4038

N-[3-(2-Fluoro-4′-{[(isoxazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4039

N-(3-{2-Fluoro-2′-methoxy-4′-[(methyl-pyridin-4-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4040

N-[3-(2-Fluoro-2′-methoxy-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4041

N-(3-{2-Fluoro-2′-methoxy-4′-[(methyl-pyridin-4-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4042

N-[3-(2-Fluoro-4′-{[(furan-3-ylmethyl)-amino]-methyl}-2′-methoxy-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4043

N-(3-{2-Fluoro-4′-[(furan-3-ylmethyl-methyl-amino)-methyl]-2′-methoxy-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4044

N-(3-{2-Fluoro-4′-[(methyl-pyridin-4-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4045

N-(3-{2-Fluoro-4′-[(methyl-pyridin-2-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4046

N-[3-(4′-{[(3,5-Dichloro-benzyl)-methyl-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4047

N-(3-{2-Fluoro-4′-[(methyl-pyridin-3-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4048

N-[3-(2-Fluoro-4′-{[(1H-pyrrol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4049

N-[3-(2-Fluoro-4′-{[(1-methyl-1H-indol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4050

1H-Indole-6-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-methyl-amide 4051

1-Methyl-1H-pyrrole-2-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-methyl-amide 4052

N-{3-[3-Fluoro-4-(5-{[(pyridin-4-ylmethyl)-amino]-methyl}-pyridin-2-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4053

N-{3-[3-Fluoro-4-(5-{[(furan-3-ylmethyl)-amino]-methyl}-pyridin-2-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4054

N-[3-(2-Fluoro-4′-{[(6-methoxy-pyridin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4055

N-[3-(2-Fluoro-4′-{[(6-methoxy-pyridin-3-ylmethyl)-methyl-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4056

N-(3-{4′-[(2,5-Bis-trifluoromethyl-benzylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4057

N-[3-(2-Fluoro-4′-{[(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4058

N-[3-(2-Fluoro-4′-{[(furan-3-ylmethyl)-amino]-methyl]-2′-methoxy-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4059

N-[3-(2-Fluoro-4′-{[(1-methyl-1H-pyrrol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4060

N-[3-(2-Fluoro-4′-{[(isoquinolin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4061

N-(3-{2-Fluoro-4′-[(furan-3-ylmethyl-methyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4062

N-(3-{4′-[(4-Dimethylamino-benzylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4063

N-(3-{4′-[(4-Chloro-benzylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4064

N-(3-{4′-[(2,4-Dichloro-benzylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4065

N-[3-(2-Fluoro-4′-{[(isoquinolin-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4066

N-[3-(2-Fluoro-4′-{[(3H-imidazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4067

N-[3-(2-Fluoro-4′-{[(3H-imidazol-4-ylmethyl)-methyl-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4068

N-[3-(2-Fluoro-4′-{[(1H-imidazol-4-ylmethyl)-(3H-imidazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4069

N-[3-(2-Fluoro-4′-{[(5-nitro-furan-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4070

N-(3-{4′-[(3-Cyano-benzylamino)-methyl]-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4071

N-[3-(2-Fluoro-4′-{[(quinolin-6-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4072

N-[3-(2-Fluoro-4′-{[(6-methyl-pyridin-2-ylmethyl)-amino]methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4073

N-{3-[3-Fluoro-4-(6-{[(pyridin-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4074

N-[3-(2-Fluoro-4′-{[(thiazol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4075

N-[3-(2-Fluoro-4′-{[(5-hydroxymethyl-furan-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4076

N-[3-(2-Fluoro-4′-{[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4077

N-[3-(4′-{[(Benzo[b]thiophen-3-ylmethyl)-amino)-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4078

N-[3-(4′-{[(5-Bromo-furan-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4079

N-(3-{2-Fluoro-4′-[(3-imidazol-1-yl-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4080

N-{3-[2-Fluoro-4′-(N-pyridin-4-ylmethyl-carbamimidoyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4081

N-[3-(2-Fluoro-4′-{[(5-methyl-furan-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4082

N-[3-(2-Fluoro-4′-{[(5-methyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4083

N-[3-(2-Fluoro-4′-{[(1H-indol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4084

N-[3-(2-Fluoro-4′-{[(5-phenyl-thiophen-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4085

N-[3-(4′-{[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4086

N-[3-(2-Fluoro-4′-{[(thiophen-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4087

N-(3-{2-Fluoro-4′-[(2-pyridin-2-yl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4088

N-[2-Oxo-3-(2,2′,3′-trifluoro-4′-{[(furan-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-oxazolidin-5-(S)-ylmethyl]-acetamide 4089

N-[2-Oxo-3-(2,2′,3′-trifluoro-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-oxazolidin-5-(S)-ylmethyl]-acetamide 4090

N-[2-Oxo-3-(2,2′,3′-trifluoro-4′-{[pyridin-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-oxazolidin-5-(S)-ylmethyl]-acetamide 4091

N-[3-(2-Fluoro-4′-{[(1H-imidazol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4092

N-[3-(4′-{[(1H-Benzoimidazol-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4093

N-(3-{2-Fluoro-4′-[(4-sulfamoyl-benzylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4094

N-[3-(2-Fluoro-4′-{[2-(4-sulfamoyl-phenyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4095

N-[3-(2-Fluoro-4′-{[(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4096

N-[3-(2-Fluoro-4′-{[2-(4-methyl-thiazol-5-yl-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4097

N-{3-[2-Fluoro-4′-(N-pyridin-2-ylmethyl-carbamimidoyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4098

N-[3-(2-Fluoro-4′-{[(5-methoxy-1H-indol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4099

N-[3-(2-Fluoro-4′-{[(3-methyl-thiophen-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4100

N-[3-(4′-{[(1-Benzenesulfonyl-1H-pyrrol-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4101

N-[3-(4′-{[(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4102

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid (pyridin-4-ylmethyl)-amide 4103

N-[3-(4′-{[(2,5-Dimethyl-furan-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4104

N-[3-(2-Fluoro-4′-{[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4105

N-[3-(2-Fluoro-4′-{[(5-methyl-2-trifluoromethyl-furan-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4106

N-{4′-[5-(R)-(Acetylamino-methyl)-4,5-dihydro-isoxazol-3-yl]-biphenyl-4-ylmethyl}-phthalamic acid 4107

N-(4-{5-[5-(R)-(Acetylamino-methyl)-4,5-(S)-dihydro-isoxazol-3-yl]-pyridin-2-yl}-benzyl)-phthalamic acid 4108

N-[3-(4′-{[(2,4-Dimethyl-thiazol-5-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4109

N-[3-(4′-{[(3,5-Dimethyl-isoxazol-4-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4110

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid (pyridin-2-ylmethyl)-amide 4111

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid (furan-2-ylmethyl)-amide 4112

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid[2-(4-methyl-thiazol-5-yl)-ethyl]-amide 4113

N-[3-(2-Fluoro-4′-{[(2-thiophen-2-yl-thiazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4114

N-[3-(2-Fluoro-4′-{[2-(2-oxo-imidazolidin-1-yl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4115

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid (2-pyridin-2-yl-ethyl)-amide 4116

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid[2-(3H-imidazol-4-yl)-ethyl]-amide 4117

N-[3-(2-Fluoro-4′-{[(2-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4118

N-[3-(2-Fluoro-4′-{[(6-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4119

N-[3-(2-Fluoro-4′-{[(5-pyridin-2-yl-thiophen-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4120

5-[({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-methyl]-2-methyl-furan-3-carboxylic acidmethyl ester 4121

N-[3-(4′-{[(Benzothiazol-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4122

N-[3-(2-Fluoro-4′-{[(2-phenyl-thiazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4123

N-[3-(2-Fluoro-4′-{[(2-phenyl-1H-imidazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4124

N-[3-(4′-{[(2-Ethyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4125

N-[3-(4′-{[(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4126

N-[3-(4′-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4127

N-[3-(2-Fluoro-4′-{[(3-thiophen-2-yl-1H-pyrazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4128

N-[3-(4′-{[(5-Cyano-6-methylsulfanyl-pyridin-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4129

N-[3-(4′-{[(2-Amino-4-oxo-4H-chromen-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4130

N-[3-(2-Fluoro-4′-{[(2-methyl-5-phenyl-furan-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4131

N-[3-(4′-{[(3,4-Dihydro-2H-pyran-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4132

N-[3-(4′-{[(Pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-4,5-dihydro-isoxazol-5-(R)-ylmethyl]-acetamide 4133

N-{3-[6-(4-{[(Pyridin-4-ylmethyl)-amino]-methyl}-phenyl)-pyridin-3-yl]-4,5-dihydro-isoxazol-5-(R)-ylmethyl}-acetamide 4134

N-{2-Oxo-3-[6-(4-{[(pyridin-4-ylmethyl)-amino]-methyl}-phenyl)-pyridin-3-yl]-oxazolidin-5-(S)-ylmethyl}-acetamide 4135

N-[3-(4′-{[(4-Amino-pyridin-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4136

N-[3-(4′-{[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonylamino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4137

N-[3-(2-Fluoro-4′-{[(thiophen-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4138

N-[3-(2-Fluoro-4′-{[(quinolin-7-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4139

N-[3-(4′-{[(4-Chloro-1-methyl-1H-pyrazol-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4140

N-[3-(2-Fluoro-4′-{[(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4141

N-[3-(2-Fluoro-4′-{[(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4142

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-isonicotinamide 4143

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid (thiazol-2-ylmethyl)-amide 4144

N-[3-(2-Fluoro-4′-{1-(R/S)-[(furan-3-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4145

N-[3-(2-Fluoro-4′-{1-(R/S)-[(thiazol-2-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4146

N-[3-(2-Fluoro-4′-{[(5-methyl-2-phenyl-2H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4147

N-(3-{2-Fluoro-4′-[(4-pyrrol-1-yl-benzylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4148

N-[3-(2-Fluoro-4′-{[3-(5-methyl-1H-pyrazol-4-yl)-propylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4149

N-[3-(2-Fluoro-4′-{2-[(pyridin-4-ylmethyl)-amino]ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4150

N-[3-(2-Fluoro-4′-{[2-(R/S)-(1-methyl-pyrrolidin-2-yl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4151

N-[3-(2-Fluoro-4′-{[(2-methoxy-pyridin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4152

N-[3-(4′-{[(2-Amino-pyridin-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4153

N-[3-(2-Fluoro-4′-{[(pyrrolidin-3-(R/S)-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4154

N-[3-(2,3′-Difluoro-4′-{[(thiazol-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4155

N-[3-(2,3′-Difluoro-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4156

N-[3-(2-Fluoro-4′-{[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4157

4-[({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-methyl]-1-cyclopropyl-2,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 4158

N-{3-[2-Fluoro-4′-({[5-(3-sulfamoyl-phenyl)-furan-2-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4159

N-(3-{2-Fluoro-4′-[(1-pyridin-4-(R/S)-yl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4160

N-(3-{2-Fluoro-4′-[1-(R/S)-(1-pyridin-4-(R/S)-yl-ethylamino)-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4161

N-[3-(4′-{[(5-Ethyl-furan-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4162

N-[3-(4′-{[(5-Ethyl-thiophen-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4163

N-[3-(2-Fluoro-4′-{[(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4164

N-[3-(2,3′-Difluoro-4′-{[([1,2,3]thiadiazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4165

N-[3-(2-Fluoro-4′-{[(2-methyl-1H-imidazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4166

N-[3-(2-Fluoro-3′-{[([1,2,3]thiadiazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4167

N-[3-(2-Fluoro-4′-{[(5-methyl sulfanyl-thiophen-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4168

N-[3-(4′-{[(4-Bromo-1-methyl-1H-pyrazol-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4169

N-[3-(4′-{[(4-Bromo-2H-pyrazol-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4170

N-{3-[4′-(Benzylsulfamoyl-methyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4171

N-[3-(2-Fluoro-4′-{2-hydroxy-1-[([1,2,3]thiadiazol-4-(R/S)-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]- acetamide4172

N-[3-(2-Fluoro-4′-{2-hydroxy-1-[([1,2,3]thiadiazol-4-(R/S)-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]- acetamide4173

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid[1-carbamoyl-2-(S)-(3H-imidazol-4-yl)-ethyl]-amide 4174

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-3-(S)-(1H-imidazol-4-yl)-propionamide 4175

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-3-(S)-(1H-indol-3-yl)-propionamide 4176

N-[3-(2-Fluoro-2′,5′-dimethyl-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4177

N-(3-{4′-[(2,2-Difluoro-2-pyridin-2-yl-ethylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4178

N-[3-(2-Fluoro-4′-{[(5-(S)-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4179

N-[3-(2-Fluoro-4′-{[(3-fluoro-pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4180

N-[3-(2-Fluoro-4′-{[(5-methylamino-[1,2,4]thiadiazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4181

N-[3-(4′-{[(6-Bromo-pyridin-3-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4182

N-[3-(4′-{[(5-Bromo-pyridin-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4183

N-(3-(2-Fluoro-4′-{[(isoxazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4184

2-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-2-(R)-[(pyridin-4-ylmethyl)-amino]-acetamide 4185

2-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-2-(R)-[(pyridin-2-ylmethyl)-amino]-acetamide 4186

N-[3-(2-Fluoro-4′-{[(piperidin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4187

5-{4-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide 4188

5-{4-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridine-2-carboxylic acid (pyridin-4-ylmethyl)-amide 4189

5-{4-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridine-2-carboxylic acid (thiazol-2-ylmethyl)-amide 4190

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-3,2′-difluoro-biphenyl-4-carboxylic acid (pyridin-2-ylmethyl)-amide 4191

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-3,2′-difluoro-biphenyl-4-carboxylic acid [2-(3H-imidazol-4-yl)-ethyl]-amide 4192

N-{3-[2-Fluoro-4′-(pyridin-2-ylmethoxymethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4193

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-acrylamide 4194

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-3-(1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-acrylamide 4195

N-(3-{3-Fluoro-4-[6-(pyridin-2-ylmethoxymethyl)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4196

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethoxymethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4197

N-(3-{3-Fluoro-4-[5-(pyridin-2-ylmethoxymethyl)-pyridin-2-yl]-phenyl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4198

N-{3-[2-Fluoro-4′-(1-oxy-pyridin-4-ylmethoxymethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4199

N-[3-(2-Fluoro-4′-{1-(R)-hydroxy-2-[(oxazol-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4200

N-[3-(2-Fluoro-4′-{2-hydroxy-1-(S)-[(oxazol-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4201

N-[3-(2-Fluoro-4′-{1-(R)-hydroxy-2-[(pyridin-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4202

N-[3-(2-Fluoro-4′-{2-hydroxy-1-(R)-[(pyridin-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4203

N-[3-(2-Fluoro-4′-{[(pyrimidin-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4204

N-(3-{4′-[(Acetyl-[1,2,3]thiadiazol-4-ylmethyl-amino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4205

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid (oxazol-4-ylmethyl)-amide 4206

N-[3-(2-Fluoro-4′-{[([1,2,4]thiadiazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4207

2-(4-Chloro-benzylamino)-thiazole-4-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4208

N-[3-(2-Fluoro-4′-{[(oxazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4209

N-[3-(4′-{[([1,3]Dioxolan-2-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4210

N-(3-{2-Fluoro-4′-[(oxiranylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4211

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4212

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethanesulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4213

3-(2-Fluoro-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-(R)-hydroxymethyl-oxazolidin-2-one 4214

N-{3-[2-Fluoro-4′-(pyridin-4-ylmethanesulfonylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4215

N-(3-{2-Fluoro-4′-[(methyl-quinolin-3-ylmethyl-amino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4216

N-{3-[2-Fluoro-4′-(pyridin-2-ylmethylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4217

N-{3-[2-Fluoro-4′-(pyridin-2-ylmethanesulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4218

N-[3-(2-Fluoro-4′-{[(1-methyl-1H-indol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4219

N-[3-(2-Fluoro-4′-{[(tetrahydro-furan-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4220

N-[3-(2-Fluoro-4′-{[(tetrahydro-furan-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4221

N-[3-(2-Fluoro-4′-{[(thiophen-2-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4222

N-{3-[2-Fluoro-4′-(N-furan-2-ylmethyl-carbamimidoyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4223

5-{4-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridine-2-carboxylic acid [2-(3H-imidazol-4-yl)-ethyl]-amide4224

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid ([1,2,4]oxadiazol-3-ylmethyl)-amide 4225

4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid ([1,2,4]thiadiazol-3-ylmethyl)-amide 4226

N-[3-(2-Fluoro-4′-oxiranylmethylsulfanylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4227

N-[3-(2-Fluoro-4′-{[2-(1H-imidazol-4-yl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4228

N-[3-(2-Fluoro-4′-{[2-(5-methyl-3H-indol-3-yl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4229

N-[3-(2-Fluoro-4′-{[(5-methyl-isoxazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4230

3-(2-Fluoro-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-(R)-[1,2,4]triazol-1-ylmethyl-oxazolidin-2-one 4231

3-(2-Fluoro-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-(R)-(1-methyl-1H-tetrazol-5-ylsulfanylmethyl)-oxazolidin-2-one 4232

N-[3-(2-Fluoro-4′-{1-(R/S)-[(pyridin-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4233

N-[3-(2-Fluoro-4′-{[([1,2,4]oxadiazol-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4234

N-[3-(2-Fluoro-4′-{[(oxazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4235

N-{3-[3-Fluoro-4-(6-{[(oxazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4236

N-(3-{2-Fluoro-4′-[N′-(pyridine-4-carbonyl)-hydrazinomethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4237

N-(3-{2-Fluoro-4′-[N′-(pyridine-3-carbonyl)-hydrazinomethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4238

N-[3-(2-Fluoro-4′-{[(oxazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4239

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl]-2-[1,2,3]triazol-1-yl-acetamide 4240

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(4-hydroxymethyl-[1,2,3]triazol-1-yl)- acetamide4241

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-[4-(2-hydroxy-butyl)-[1,2,3]triazol-1-yl]-acetamide 4242

2-Methyl-thiazole-4-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4243

2-Methyl-thiazole-4-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4244

N-{3-[2-Fluoro-4′-([1,2,4]oxadiazol-3-ylmethylsulfanylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4245

N-[3-(2-Fluoro-4′-{[(1-oxy-pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4246

N-{3-[4′-(2-Benzylamino-1-(S)-hydroxy-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4247

N-{3-(4′-{2-[Benzyl-(3-fluoro-propyl)-amino]-1-(S)-hydroxy-ethyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4248

N-[3-(4′-{2-[Benzyl-(2-methylsulfanyl-ethyl)-amino]-1-(S)-hydroxy-ethyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4249

N-[3-(4′-{2-[Benzyl-(3-chloro-3,3-difluoro-propyl)-amino]-1-(S)-hydroxy-ethyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4250

N-(2-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-2-(S)-hydroxy-ethyl)-N-benzyl-acetamide 4251

N-(3-{4′-[2-(Benzyl-methyl-amino)-1-(S)-hydroxy-ethyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4252

N-{3-[3-Fluoro-4-(6-{[(isoxazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4253

N-[3-(4′-{[(3-Bromo-isoxazol-5-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4254

N-[3-(2-Fluoro-4′-{2-[(isoxazol-4-ylmethyl)-amino]-1-methoxyimino-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4255

N-[3-(2-Fluoro-4′-{1-methoxyimino-2-[(oxazol-4-ylmethyl)-amino]-ethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4256

N-[3-(4′-{[3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-propylamino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4257

N-[3-(2-Fluoro-4′-{[(2-fluoro-pyridin-3-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4258

N-[3-(2-Fluoro-4′-{[3-(3H-[1,2,3]triazol-4-yl)-propylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4259

N-(3-{2-Fluoro-4′-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4260

N-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-3-(5-pyrimidin-2-yl-pyridin-2-yl)-propionamide 4261

N-[3-(2-Fluoro-2′-methoxy-4′-{[(pyridin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4262

N-(3-{2-Fluoro-4′-[(2-[1,2,3]triazol-1-yl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4263

N-{3-[4′-(Benzyloxyamino-methyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4264

N-(3-{2-Fluoro-4′-[(3-[1,2,3]triazol-1-yl-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4265

N-[3-(4′-{[Benzyloxy-(3-fluoro-propyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4266

N-[3-(2-Fluoro-4′-{[2-(3H-[1,2,3]triazol-4-yl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4267

N-[3-(2-Fluoro-4′-{[(3H-[1,2,3]triazol-4-ylmethyl)-amino]methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4268

3-(2-Fluoro-4′-{[(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-(R)-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 4269

N-[3-(2-Fluoro-4′-{[(5-methyl-3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4270

N-[3-(4′-{[Bis-(5-methyl-3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4271

N-(3-{2-Fluoro-4′-[N′-(4-methyl-[1,2,3]thiadiazole-carbonyl)-hydrazinomethyl}-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4272

N-[3-(2-Fluoro-4′-{[(3-methyl-3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4273

N-[3-(2-Fluoro-4′-{[(2-methyl-2H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4274

N-(3-{2-Fluoro-4′-[(3-fluoro-2-[1,2,3]triazol-1-yl-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4275

N-[3-(2-Fluoro-4′-{[2-(4-fluoro-phenyl)-2-(R/S)-hydroxy-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4276

N-[3-(2-Fluoro-4′-{[methyl-(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4277

N-{3-[3-Fluoro-4-(6-{[(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4278

N-[3-(2-Fluoro-4′-{[1-(R/S)-(3H-[1,2,3]triazol-4-yl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4279

N-[3-(2-Fluoro-4′-{[(pyrrolidin-2-(R/S)-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4280

{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluorobiphenyl-4-ylmethyl}-(1-methyl-1H-tetrazol-5-ylmethyl)-carbamic acidtert-butyl ester 4281

{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(2-methyl-2H-tetrazol-5-ylmethyl)-carbamic acidtert-butyl ester 4282

N-[3-(2-Fluoro-4′-{[(1H-tetrazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4283

N-[3-(2-Fluoro-4′-{[(1-methyl-1H-tetrazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4284

N-[3-(2-Fluoro-4′-{[(2-methyl-2H-tetrazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4285

N-[3-(2-Fluoro-4′-{[(N-hydroxy-pyridine-4-carboximidoyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4286

N-[3-(4′-{2-[Benzyl-(2-methanesulfonyl-ethyl)-amino]-1-(S)-hydroxy-ethyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4287

N-[3-[4′-{[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonylamino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 4288

N-{3-[4′-(Benzylsulfamoyl-methyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide 4289

5-Oxo-pyrrolidine-2-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4290

3-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-azetidine-1-carboxylic acid tert-butylester 4291

Azetidine-3-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4292

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(R)-amino-3-(3H-imidazol-4-yl)-propionamide 4293

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-2-pyridin-3-yl-acetamide 4294

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-amino-2-pyridin-3-yl-acetamide 4295

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-azetidine-1-carboxylic acid tert-butylester 4296

Azetidine-2-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4297

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(R)-amino-2-(4-fluoro-phenyl)-acetamide 4298

4-[({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butylester 4299

N-{3-[2-Fluoro-4′-(1-[1,2,3]thiadiazol-4-ylmethyl-ureidomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 4300

N-(3-{4′-[(Cyclopropylmethyl-amino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4301

4-(R)-Hydroxy-pyrrolidine-2-(S)-carboxylicacid {4-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4302

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(S)-amino-3-pyridin-2-yl-propionamide 4303

[1-(S)-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-2-pyridin-2-yl-ethyl]-carbamicacid tert-butyl ester 4304

[1-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-cyclopropyl]-carbamic acid tert-butylester 4305

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-2,5-dihydro-pyrrole-1-(S)-carboxylicacid tert-butylester 4306

2,5-Dihydro-1H-pyrrole-2-(S)-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4307

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(R)-amino-3-(1H-indol-3-yl)-propionamide 4308

[1-(R)-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-2-(1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester 4309

Pyrrolidine-2-(S)-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4310

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(R)-amino-3-pyridin-3-yl-propionamide 4311

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-carbamoyl)-4-(R)-hydroxy-pyrrolidine-1-(S)-carboxylic acid tert-butyl ester 4312

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-3-(S)-(1H-indol-3-yl)-propionamide 4313

2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-3-(1H-imidazol-4-yl)-propionamide 4314

N-(3-{2-Fluoro-4′-[(2-oxo-2-piperazin-1-yl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4315

4-[2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-acetyl]-piperazine-1-carboxylic acidtert-butyl ester 4316

N-(3-{2-Fluoro-4′-[(2-morpholin-4-yl-2-oxo-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4317

3-[({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-methyl]-pyrrolidine-1-carboxylic acidtert-butyl ester 4318

N-(3-{2-Fluoro-4′-[(2-morpholin-4-yl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4319

Cyclopropanecarboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4320

N-(3-{2-Fluoro-4′-[(furan-3-ylmethyl-methyl-amino)-methyl]-2′-methoxy-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 4321

1-Amino-cyclopropanecarboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 4322

Piperazine-2-(R/S)-carboxylic acid {4′-[5-(S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amide 5001

N-[3-(2-Fluoro-4′-{[2-(3H-[1,2,3]triazol-4-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5002

N-[3-(2-Fluoro-4′-{[3-(3H-[1,2,3]triazol-4-ylsulfanyl)-propylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5003

N-[3-(2-Fluoro-4′-{[2-([1,3,4]thiadiazol-2-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5004

N-[3-(2-Fluoro-4′-{[2-(pyridin-2-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5005

N-[3-(2-Fluoro-4′-{[2-(4H-[1,2,4]-triazol-3-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5006

N-[3-(2-Fluoro-4′-{[2-(thiazol-2-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5007

3-(2-Fluoro-4′-{[2-(3H-[1,2,3]triazol-4-ylsulfanyl)-ethylaminol]-methyl}-biphenyl-4-yl)-5-(R)-[1,2,3]triazol-1-ylmethyl-oxazolidin-2- one5008

N-[3-(2-Fluoro-4′-{[2-(1H-imidazol-2-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5009

N-[3-(2-Fluoro-4′-{[2-(pyrimidin-2-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5010

2-[2-({4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-ethylsulfanyl]-1H-imidazole-4-carboxylic acid ethyl ester 5011

N-[3-(2-Fluoro-4′-{[2-(S)-(hydroxy-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-propylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 5012

N-(3-{2-Fluoro-4′-[(3-pyridin-4-yl-ureido)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 5013

N-(3-{2-Fluoro-4′-[3-(3-fluoro-phenyl)-ureidomethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 5014

N-{4′-[5-(S)-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-(2,4-dichloro-phenoxy)-acetamide 5015

N-[3-(4′-{[3-(3-Chloro-5-trifluoromethyl-pyridin-2-ylamino)-propylamino]-methyl}-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-(S)-ylmethyl]-acetamide 6001

N-(3-{2-Fluoro-4′-[3-(3-imidazol-1-yl-propyl)-ureido]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 6002

N-{3-[2-Fluoro-4′-(3-thiazol-2-ylmethyl-ureido)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 6003

N-(3-{2-Fluoro-4′-[3-(2-pyridin-2-yl-ethyl)-ureido]-biphenyl-4-yl}-2-oxo-oxazolidin-5-(S)-ylmethyl)-acetamide 6004

N-{3-[2-Fluoro-4′-(3-pyridin-4-ylmethyl-ureido)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 6005

N-{3-[2-Fluoro-4′-(3-pyridin-2-ylmethyl-ureido)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide 6006

N-{3-[2-Fluoro-4′-(3-pyridin-4-yl-ureido)-biphenyl-4-yl]-2-oxo-oxazolidin-5-(S)-ylmethyl}-acetamide

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

Example 1 Synthesis of Biaryl Precursors

Scheme 1 depicts the synthesis of various biaryl intermediates useful inproducing compounds of the present invention. Known iodoaryloxazolidinone intermediate 50 (see U.S. Pat. Nos. 5,523,403 and5,565,571) is coupled to a substituted aryl boronic acid (the Suzukireaction) to produce biaryl alcohol 51. Mesylate 52, azide 53, and amine54 are then synthesized using chemistry well known to those skilled inthe art.

Synthesis of Alcohol 51

A suspension ofN-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 50(14.0 g, 37 mmol) in toluene (120 mL) was treated with4-(hydroxymethyl)phenylboronic acid (7.87 g, 51.8 mmol, 1.4 equiv),potassium carbonate (K₂CO₃, 15.32 g, 111 mmol, 3.0 equiv), ethanol(EtOH, 40 mL), and H₂O (40 mL) at 25° C., and the resulting mixture wasdegassed three times under a steady stream of argon at 25° C.Tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄, 2.14 g, 1.85 mmol,0.05 equiv) was subsequently added to the reaction mixture, and theresulting reaction mixture was degassed three times again before beingwarmed to gentle reflux for 6 h. When thin layer chromatography (TLC)and HPLC showed the coupling reaction was complete, the reaction mixturewas cooled to room temperature before being treated with H₂O (240 mL).The resulting mixture was then stirred at room temperature for 10 minbefore being cooled to 0-5° C. for 1 h. The solid precipitates werecollected by filtration, washed with H₂O (2×100 mL) and 20% ethylacetate (EtOAc)/hexane (2×50 mL), and dried in vacuo. The crude desiredN-[3-(2-Fluoro-4′-hydroxymethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide51 (12.50 g, 94% yield) was obtained as off-white solids. This materialwas found to be essentially pure by HPLC and ¹H NMR and was directlyused in the subsequent reaction without further purification. ¹H NMR(300 MHz, DMSO-d₆) δ 1.76 (s, 3H, COCH₃), 3.35 (t, 2H, J=5.4 Hz), 3.69(dd, 1H, J=6.4, 9.2 Hz), 4.08 (t, 1H, J=9.1 Hz), 4.46 (d, 2H, J=5.7 Hz,CH₂OH), 4.68 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.25-7.52 (m, 7H,aromatic-H), 8.18 (t, 1H, J=5.8 Hz, NHCOCH₃). LCMS (ESI) m/e 359 (M+H)⁺.

Synthesis of Mesylate 52

A suspension of 51 (12.49 g, 34.90 mmol) in methylene chloride (CH₂Cl₂,150 mL) was treated with triethylamine (Et₃N, 7.07 g, 9.7 mL, 70 mmol,2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C.before being treated dropwise with methanesulfonyl chloride (4.80 g,3.24 mL, 41.9 mmol, 1.2 equiv) at 0-5° C. The resulting reaction mixturewas subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showedthe reaction was complete, the reaction mixture was treated with H₂O(100 mL) at 0-5° C. The mixture was then concentrated in vacuo to removemost of the CH₂Cl₂, and the resulting slurry was treated with H₂O (150mL). The mixture was stirred at room temperature for 10 min before beingcooled to 0-5° C. for 30 min. The solid precipitates were collected byfiltration, washed with H₂O (2×100 mL) and 20% EtOAc/hexane (2×50 mL),and dried in vacuo. The crude desired methanesulfonic acid4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethylester 52 (11.84 g, 78% yield) was obtained as off-white solids, which byTLC and HPLC was found to be essentially pure and was directly used inthe subsequent reaction without further purification. LCMS (ESI) m/e 437(M+H)⁺.

Synthesis of Azide 53

A solution of 52 (9.27 g, 21.26 mmol) in anhydrous N,N-dimethylformamide(DMF, 50 mL) was treated with sodium azide (NaN₃, 5.53 g, 85.04 mmol,4.0 equiv) at 25° C., and the resulting reaction mixture was warmed to70-80° C. for 4 h. When TLC and HPLC showed the reaction was complete,the reaction mixture was cooled to room temperature before being treatedwith H₂O (150 mL). The resulting mixture was stirred at room temperaturefor 10 min before being cooled to 0-5° C. for 1 h. The solidprecipitates were collected by filtration, washed with H₂O (2×100 mL)and 20% EtOAc/hexane (2×50 mL), and dried in vacuo. The crude desiredN-[3-(4′-azidomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide53 (7.16 g, 88% yield) was obtained as off-white solids. The materialwas found to be essentially pure by TLC and HPLC and was directly usedin the subsequent reaction without further purification. LCMS (ESI) m/e384 (M+H)⁺.

Synthesis of Amine 54

A solution of 53 (7.16 g, 18.69 mmol) in tetrahydrofuran (THF) (100 mL)was treated with triphenylphosphine (PPh₃, 5.88 g, 22.43 mmol, 1.2equiv) and H₂O (3.6 g, 3.6 mL, 0.2 mmol, 11.0 equiv) at 25° C., and theresulting reaction mixture was warmed to 50-55° C. for 12 h. When TLCand HPLC showed the reduction reaction was complete, the reactionmixture was cooled to room temperature before the solvents were removedin vacuo. The residue was directly purified by flash columnchromatography (0-15% MeOH—CH₂Cl₂ gradient elution) to afford thedesiredN-[3-(4′-Aminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide54 (5.82 g, 87% yield) as off-white crystals, which were of sufficientpurity to be directly used in subsequent reactions. ¹H NMR (300 MHz,DMSO-d₆) δ 1.85 (s, 3H, COCH₃), 3.04 (br. s, 2H, NH₂), 3.44 (t, 2H,J=5.4 Hz), 3.78 (m, 3H), 4.18 (t, 1H, J=9.1 Hz), 4.77 (m, 1H), 7.25-7.60(m, 7H, aromatic-H), 8.20 (t, 1H, J=5.8 Hz, NHCOCH₃). LCMS (ESI) m/e 359(M+2H)²⁺.

Example 2 Synthesis of Triazole 1001 and Imidazole 1002

Scheme 2 illustrates the synthesis of triazole 1001 and imidazole 1002.Aryl bromide 60 was converted to boronic acid 61 which was used in aSuzuki coupling with aryl iodide 50 to afford alcohol 63 afterdesilylation. The alcohol was converted to mesylate 64 and then to azide65. The cycloaddition of azide 65 with trimethylsilylacetylene followedby desilylation afforded triazole 1001. Alkylation of mesylate 64 withimidazole yielded compound 1002.

Synthesis of Bromide 60

To a solution of 4-bromophenethyl alcohol (5.60 g, 27.9 mmol), imidazole(3.80 g, 55.7 mmol) and a catalytic amount of 4-dimethylaminopyridine(DMAP) in DMF (55 mL) was added t-butyldiphenylchlorosilane (TBDPSCl,7.20 mL, 27.9 mmol) at 0° C. and the mixture was stirred at ambienttemperature for 72 h. The reaction was quenched with ice cold water (50mL) and extracted with ether (4×50 mL). The combined etheral layer waswashed with water (4×100 mL), dried over anhydrous sodium sulfate(Na₂SO₄), concentrated and purified by flash chromatography (2% ethylacetate in hexanes) to yield 10.6 g of 60.

Synthesis of Boronic Acid 61

To a solution of 60 (10.5 g, 24.0 mmol) in THF (50 mL) was added n-butyllithium (n-BuLi, 2.5M in hexane, 11.5 mL, 28.8 mmol) at −78° C. and themixture was stirred for 1 h before the addition of trimethyl borate(3.54 mL, 31.2 mmol). The solution was then stirred overnight at ambienttemperature and quenched with 1M potassium hydrogen sulfate (KHSO₄, 25mL). The resulting mixture was extracted with CH₂Cl₂ (3×50 mL), washedwith brine (3×100 mL), dried (anhydrous Na₂SO₄), concentrated andpurified by flash chromatography (25% ethyl acetate in hexanes) to yield5 g of boronic acid 61 as mixture of acid and cyclic anhydrides.

Synthesis of Alcohol 63

To a mixture of boronic acid 61 (4.7 g, 11.7 mmol), known oxazolidinone50 (4.00 g, 10.6 mmol; see U.S. Pat. Nos. 5,523,403 and 5,565,571),potassium carbonate (K₂CO₃, 4.40 g, 31.8 mmol) and Pd(PPh₃)₄ (0.613 g, 5mol %) was added toluene (90 mL), ethanol (30 mL) and H₂O (30 mL). Thereaction mixture was refluxed overnight under argon atmosphere,concentrated and redissolved in CH₂Cl₂ (100 mL). The organic phase waswashed with brine solution (2×100 mL), dried (anhydrous Na₂SO₄),concentrated and used for the next step without further purification. Toa solution of this crude material in THF (70 mL) was addedtetrabutylammonium fluoride (TBAF, 20 mL, 20 mmol) and the mixture wasstirred overnight at ambient temperature. The reaction mixture wasconcentrated and washed with water (4×100 mL) to yield 3.5 g of 63. LCMS(ESI) m/z 373 (M+H).

Synthesis of Mesylate 64 and Azide 65

To a solution of 63 (1.0 g, 2.7 mmol) in CH₂Cl₂ (15 mL), DMF (4 mL) andN,N-diisopropylethylamine (Hunig's base, 0.75 mL, 4.05 mmol) was addedmethanesulfonyl chloride (0.32 mL, 2.7 mmol) at 0° C. After 2 h thereaction mixture was poured into CH₂Cl₂ (150 mL) and the organic layerwas washed with water (3×100 mL), dried, concentrated to afford 64 as asolid. The crude solid 64 thus obtained was heated with NaN₃ (0.35 g,5.4 mmol) at 90° C. overnight. The reaction mixture was poured intoethyl acetate (100 mL). The ethyl acetate layer was washed with water(3×50 mL), dried and concentrated to yield 1.1 g of pure azide 65. LCMS(ESI) m/z 398 (M+H).

Synthesis of Triazole 1001

A solution of azide 65 (100 mg, 0.252 mmol) and trimethylsilylacetylene(0.072 mL, 0.504 mmol) in DMF (3 mL) was heated at 90° C. until theazide was consumed. The reaction mixture was concentrated and treatedwith TBAF (1 mL, 1 mmol) and acetic acid (0.028 mL, 0.504 mmol) in THF(3 mL). The solution was stirred for 72 h and concentrated. The crudeproduct was purified by flash chromatography using 4% methanol (MeOH) inCH₂Cl₂ to yield 85 mg of 1001. LCMS (ESI) m/z 424 (M+H).

Synthesis of Imidazole 1002

To a solution of imidazole (70 mg, 1.0 mmol) in DMF (5 mL) was addedsodium hydride (NaH, 60%, 41 mg, 1 mmol) at 0° C. and the mixture wasstirred for 30 minutes before the addition of mesylate 64 (114 mg, 0.250mmol). The resulting solution was heated to 80° C. for 3 h, concentratedand purified by flash chromatography (5% MeOH in CH₂Cl₂). Aftertrituration with ether, the residue afforded 40 mg of 1002. LCMS (ESI)m/z 423 (M+H).

Example 3 Synthesis of Piperazines 1003-1006

Scheme 3 illustrates the synthesis of compounds 1003-1006. Mesylate 52served as alkylating agent for piperazine intermediates 68, 69 and 70 toafford compounds 1003, 1004 and 1006 respectively. Mesylate 67 wasemployed to alkylate piperazine intermediate 69 to provide compound1005.

Synthesis of Mesylate 67

Mesylate 67 was synthesized by coupling iodide 50 and4-formyl-3-fluorophenylboronic acid following the procedure describedabove for the synthesis ofN-[3-(2-fluoro-4′-hydroxymethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(see Example 1). The biaryl aldehyde obtained (1.0 g, 2.67 mmol) wassuspended in 40 mL methanol and the mixture was cooled to 0° C. Sodiumborohydride (0.112 g, 2.943 mmol) was added, and the mixture was stirredfor 50 min. Water was added (20 mL), and after stirring another 20 minthe mixture was partitioned between methylene chloride and brine. Theaqueous phase was extracted twice with methylene chloride. The aqueousphase was acidified to pH 7, then extracted twice with methylenechloride. The combined organic phase was washed with brine, dried overNa₂SO₄, and concentrated. The crude material was azeotroped with tolueneto afford the expected alcohol (900 mg).

The above alcohol (900 mg) was dissolved in methylene chloride (20 mL),DMF (13 mL) and Hunig's base (1.23 mL) and the mixture was cooled to 0°C. Methanesulfonyl chloride (557 uL, 7.20 mmol) was added and themixture was stirred for 1.5 h at 0° C. LCMS indicated a mixture ofdesired mesylate and some of the corresponding benzyl chloride. Themixture was stirred for another 30 min and then concentrated. Theresidue was treated with 400 mL water, and the precipitate was filteredand washed with water. Drying under vacuum overnight yielded 750 mgcrude mesylate 67 (as a mixture with some of the correspondingchloride).

Synthesis of Piperazine 68

A solution of tert-butyl-1-piperazine carboxylate (1 g, 5.4 mmol),bromoacetamide (820 mg, 5.94 mmol) and Hunig's base (1.2 mL, 7.2 mmol)in a mixture of CH₂Cl₂ (10 mL) and MeOH (10 mL) was heated to reflux for4 h. The reaction mixture was concentrated and the crude product thusobtained was purified by flash chromatography (19:1:0.01CH₂Cl₂/MeOH/NH₄OH) to yield 1.3 g of pure BOC-protected piperazinylacetamide. To a solution of the acetamide (250 mg, 1 mmol) in CH₂Cl₂ (10mL) was added trifluoroacetic acid (TFA, 5 mL) at 0° C. and the mixturewas stirred at that temperature for 2 h. The reaction mixture wasconcentrated to yield 68 which was used for subsequent reactions withoutfurther purification.

Synthesis of Piperazine 69

A solution of tert-butyl-1-piperazine carboxylate (1 g, 5.4 mmol),bromoacetonitrile (0.5 mL, 5.94 mmol) and Hunig's base (1.2 mL, 7.2mmol) in a mixture of CH₂Cl₂ (10 mL) and MeOH (10 mL) was stirred atambient temperature for 4 h. The reaction mixture was concentrated andthe crude product thus obtained was purified by flash chromatography(19:1:0.01 CH₂Cl₂/MeOH/NH₄OH) to yield 1.3 g of pure BOC-protectedpiperazinyl acetonitrile. To a solution of the piperazinyl acetonitrile(300 mg, 1.3 mmol) in CH₂Cl₂ (10 mL) was added TFA (5 mL) at 0° C. andthe mixture was stirred at that temperature for 2 h. The reactionmixture was concentrated to yield 69 which was used for subsequentreactions without further purification.

Synthesis of Compound 1003

A solution of mesylate of 52 (138 mg, 0.320 mmol) and 68 (˜1 mmol) inHunig's base (2 mL) and DMF (8 mL) was heated to 90° C. for 2 h. Thenthe solution was concentrated and purified by flash chromatography oversilica gel (20:1:0.01 CH₂Cl₂/MeOH/NH₄OH) to yield 1003. LCMS (ESI) m/z484 (M+H)⁺.

Synthesis of Compound 1004

Compound 1004 was synthesized from mesylate 52 and piperazineintermediate 69 in the same manner as described above for the synthesisof compound 1003. LCMS (ESI) m/z 466 (M+H)⁺.

Synthesis of Compound 1005

Compound 1005 was synthesized from mesylate 67 and piperazineintermediate 69 in the same manner as described above for the synthesisof compound 1003. LCMS (ESI) m/z 484 (M+H)⁺.

Synthesis of Compound 1006

Compound 1006 was synthesized from mesylate 52 and available piperazineintermediate 70 in the same manner as described above for the synthesisof compound 1003. LCMS (ESI) m/z 455 (M+H)⁺.

Example 4 Synthesis of Compounds 1007-1010

Scheme 4 illustrates the synthesis of compounds 1007-1010. Mesylate 52was converted to nitrile 71, which was subsequently transformed totetrazole 1007. Mesylate 52 served as alkylating agent for the anionderived from imidazole to afford imidazole derivative 1008. Mesylate 67was converted to azide 72, which was then subsequently converted totriazole 1009. Mesylate 67 served as alkylating agent for the anionderived from imidazole to afford imidazole derivative 1010.

Synthesis of Tetrazole 1007

To a solution of mesylate 52 (2.0 g, 4.6 mmol) in DMF (30 mL) was addedsodium cyanide (NaCN, 0.45 g, 9.2 mmol) and the mixture was heated to70° C. for 3 h. The reaction mixture was cooled to ambient temperatureand poured into water (800 mL). The solid thus obtained was filtered andpassed through a small bed of silica gel (CH₂Cl₂: MeOH=12:1) to yield1.8 g of nitrile 71. LCMS (ESI) m/z 368 (M+H)⁺.

A mixture of 71 (100 mg, 0.272 mmol), NaN₃ (40 mg, 0.598 mmol) andammonium chloride (NH₄Cl, 32 mg, 0.598 mmol) in DMF (2 mL) was heated to90° C. for 3 days. The reaction mixture was concentrated and purified byflash chromatography (10% MeOH in CH₂Cl₂) to yield 35.6 mg of tetrazole1007. LCMS (ESI) m/z 411 (M+H)⁺.

Synthesis of Imidazole 1008

To a solution of imidazole (37.4 mg, 0.550 mmol) in DMF (5 mL) was addedNaH (60%, 20 mg, 0.50 mmol) at 0° C. and the mixture was stirred for 30minutes before the addition of mesylate 52 (200 mg, 0.459 mmol). Theresulting solution was heated to 60° C. for 2 h and poured into water(75 mL). The aqueous suspension was extracted with 10% MeOH in CH₂Cl₂(3×75 mL) and the combined organic layer was washed with saturated NH₄Clsolution (2×100 mL). The organic layer was dried (anhydrous Na₂SO₄),concentrated and triturated with ether to yield 170 mg of imidazole1008. LCMS (ESI) m/z 409 (M+H)⁺.

Synthesis of Azide 72

Crude mesylate 67 (100 mg, 0.224 mmol; as a mixture with somecorresponding benzyl chloride) was dissolved in DMF (10 mL) and sodiumazide (114.6 mg, 1.762 mmol) was added. The mixture was stirred at roomtemperature for 14 h, and then partitioned between ethyl acetate andwater. The organic phase was washed with water, dried over Na₂SO₄, andconcentrated to provide azide 72 as a solid (190 mg).

Synthesis of Triazole 1009

Compound 1009 was synthesized from azide 72 and trimethylsilylacetylenein the same manner as described above for the synthesis of triazole1001. LCMS (ESI) m/z 428 (M+H)⁺.

Synthesis of Imidazole 1010

Compound 1010 was synthesized from mesylate 67 and imidazole in the samemanner as described above for the synthesis of imidazole derivative1008. LCMS (ESI) m/z 427 (M+H)⁺.

Example 5 Synthesis of Compounds 1011-1015

Scheme 5 illustrates the synthesis of compounds 1011-1015. Thecycloaddition of azide 53 with alkynes 74-76 afforded triazoles1011-1013 respectively. The cycloaddition of azide 53 with alkyne 77gave BOC-protected intermediate 78 which was subsequently cleaved toprovide derivative 1014. The cycloaddition of azide 53 withtrimethylsilylacetylene, followed by desilylation, yielded triazole1015.

Synthesis of Triazole 1011

A solution of azide 53 (0.10 g, 0.26 mmol) in propargyl amine 74 (0.50mL) was treated with copper iodide (0.05 g, 0.26 mmol) and was stirredat 23° C. for 0.5 h. The reaction mixture was diluted with CH₂Cl₂ andMeOH and purified by flash chromatography and preparative TLC to afford1011 as a brown solid (0.027 g; 24%). LCMS (ESI) m/z 439 (M+H)⁺.

Synthesis of Triazole 1012

A solution of azide 53 (0.10 g, 0.26 mmol) in N-methylpropargyl amine 75(0.50 mL) was treated with copper iodide (5.00 mg, 0.026 mmol) andstirred at 23° C. for 12 h. The solvent was removed in vacuo, and thecrude product was purified by preparative TLC to afford 1012 as a brownsolid (0.038 g; 32%). LCMS (ESI) m/z 453 (M+H)⁺.

Synthesis of Triazole 1013

A solution of azide 53 (0.10 g, 0.26 mmol) in N,N-dimethylpropargylamine 76 (0.056 mL, 0.520 mmol) was treated with copper iodide (5.00 mg,0.026 mmol) and stirred at 23° C. for 12 h. The solvent was removed invacuo, and the crude product was purified by flash chromatography toafford 1013 as a yellow film (0.073 g; 60%). LCMS (ESI) m/z 467 (M+H)⁺.

Synthesis of Alkyne 77

A solution of propargyl amine 74 (0.34 mL, 5.0 mmol) in methylenechloride (25 mL) was treated with BOC-glycine (0.96 g, 5.5 mmol) andEDCI (1.1 g, 5.5 mmol) and stirred at 23° C. for 0.5 h. The reactionmixture was diluted with CH₂Cl₂, washed with 1.0 M HCl (aqueous), washedwith saturated aqueous sodium bicarbonate (NaHCO₃), dried over Na₂SO₄,and the solvent evaporated in vacuo to afford alkyne 77 (0.51 g; 48%).

Synthesis of Triazole 1014

A solution of azide 53 (0.15 g, 0.39 mmol) in THF (2 mL) was treatedwith alkyne 77 (0.17 g, 0.78 mmol) and copper iodide (7.00 mg, 0.039mmol) and stirred at 23° C. for 16 h. The solvent was removed in vacuo,and the crude product was purified by flash chromatography to afford 78as a white powder (0.16 g; 68%). LCMS (ESI) m/z 618 (M+Na)⁺.

A solution of 78 (0.15 g, 0.25 mmol) was treated with HCl (1.3 mL of 4.0M solution in dioxane) and was stirred at 23° C. for 2 h. The solventwas removed in vacuo, and the residue twice redissolved in methylenechloride and evaporated to afford 1014 as a white film (0.14 g, 100%).LCMS (ESI) m/z 496 (M+H)⁺.

Synthesis of Triazole 1015

A solution of azide 53 (0.75 mg, 2.0 mmol) in DMF (10 mL) was treatedwith trimethylacetylene (2.3 mL, 20 mmol) and was stirred at 90° C. for12 h. The reaction mixture was cooled to 23° C. and the solvent wasremoved in vacuo to afford the expected silyl-substituted triazole as abrown foam (0.24 mg; 25%). LCMS (ESI) m/z 482 (M+H)⁺.

A solution of the above silyl-substituted triazole (0.050 g, 0.10 mmol)in THF (0.20 mL) was treated with acetic acid (6 μL, 0.10 mmol) andtetrabutylammonium fluoride (0.21 mL of 1.0 M solution in THF) and wasstirred at 23° C. for 16 h. The reaction mixture was diluted withCH₂Cl₂, washed with water, dried (Na₂SO₄), and the solvent removed invacuo. The crude product was purified to afford 1015 as a white powder(0.020 g; 47%). LCMS (ESI) m/z 432 (M+Na)⁺.

Example 6 Synthesis of Compounds 1016-1017

Scheme 6 illustrates the synthesis of compounds 1016-1017.Hydroxyamidine 79 was converted to bromide 80 which was subsequentlycoupled to boronate 81 to afford compound 1016. Hydroxyamidine 79 wastransformed to oxadiazole 82, which was coupled to boronate 81 to affordcompound 1017.

Synthesis of Hydroxyamidine 79

A solution of 4-bromophenylacetonitrile (10 g, 54 mmol) in methanol (100mL) was treated with sodium bicarbonate (2.2 g, 57 mmol) andhydroxylamine hydrochloride (4.0 g, 57 mmol) and refluxed for 1.5 h.Additional sodium bicarbonate (0.21 g, 5.4 mmol) and hydroxylaminehydrochloride (0.38 g, 5.4 mmol) were added, and the reaction mixturewas refluxed for 12 h. The reaction mixture was cooled to 23° C. and thesolvent removed in vacuo to afford hydroxyamidine 79 as a blue powder(4.0 g; 34%).

Synthesis of Bromide 80

A solution of hydroxyamidine 79 (0.20 g, 0.91 mmol) in 1,4-dioxane (1mL) was treated with 1,1′-carbonyldiimidazole (0.18 g, 1.1 mmol) anddiazabicycloundecene (DBU, 0.15 mL, 0.97 mmol) and stirred at 105° C.for 1 h. The reaction mixture was diluted with water and extracted withethyl acetate. The water layer was treated with 1.0 M HCl (aqueous)until the pH was 2, and then extracted with ethyl acetate. The organiclayer was dried over Na₂SO₄, and the solvent removed in vacuo to affordbromide 80 as a yellow powder (0.11 g; 49%).

Synthesis of Boronate 81

A suspension ofN-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide 62(20.0 g, 52.8 mmol) in anhydrous 1,4-dioxane (130 mL) was treated with4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol)and triethylamine (16.0 g, 22.4 mL, 158.4 mmol) at room temperature, andthe resulting reaction mixture was degassed three times under a steadystream of argon before being treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)(Pd(dppf)₂Cl₂, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. Thereaction mixture was then degassed three times again under a steadystream of argon before being heated to reflux for 7 h. When TLC and LCMSshowed that the reaction was complete, the reaction mixture was cooleddown to room temperature before being treated with water (100 mL) andethyl acetate (100 mL). The two layers were separated, and the aqueouslayer was extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with water (2×50 mL) and saturated aqueous NaClsolution (50 mL), dried over magnesium sulfate (MgSO₄), and concentratedin vacuo. The residual brown oil was further dried in vacuo to affordthe crude desiredN-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide81 (18.8 g, 20.0 g theoretical, 94%) as a brown solid which was ofsufficient purity to be used in subsequent reactions.

Synthesis of Compound 1016

A solution of boronate ester 81 (0.085 g, 0.220 mmol), bromide 80 (0.055g, 0.220 mmol), and potassium carbonate (0.12 g, 0.90 mmol) in dioxane(1.4 mL), ethanol (0.46 mL) and water (0.46 mL) was degassed and treatedwith Pd(dppf)Cl₂ (6.0 mg, 6.7 μmol), degassed again, and heated at 80°C. for 1.5 h. The reaction mixture was diluted with CH₂Cl₂ and water,and the precipitate in the water layer was recovered by vacuumfiltration to afford 1016 as a grey powder (0.034 g; 36%). LCMS (ESI)m/z 427 (M+H)⁺.

Synthesis of Bromide 82

A solution of hydroxyamidine 79 (0.25 g, 1.1 mmol) in pyridine (5 mL)was cooled to 0° C. and treated with a solution of acetic anhydride(0.11 mL, 1.1 mmol) in pyridine (5 mL) and then stirred at 120° C. for1.5 h. The reaction mixture was diluted with ethyl acetate, washed with1.0 M HCl (aqueous), washed with saturated aqueous sodium bicarbonate,dried over Na₂SO₄, and the solvent evaporated in vacuo. The crudeproduct was purified by flash chromatography to afford bromide 82 as aclear film (0.10 g; 36%).

Synthesis of Compound 1017

A solution of boronate ester 81 (0.15 g, 0.40 mmol), bromide 82 (0.10 g,0.40 mmol), and potassium carbonate (0.22 g, 1.6 mmol) in dioxane (2.5mL), ethanol (0.83 mL) and water (0.83 mL) was degassed and treated withPd(dppf)Cl₂ (10.0 mg, 0.012 mmol), degassed again, and stirred at 80° C.for 2 h. The reaction mixture was diluted with CH₂Cl₂ and washed withwater. The water layer was extracted with 2×CH₂Cl₂, dried over Na₂SO₄,and the solvent evaporated in vacuo. The crude product was purified byflash chromatography and preparative TLC to afford 1017 as a whitepowder (0.054 g; 32%). LCMS (ESI) m/z 425 (M+H)⁺.

Example 7 Synthesis of Compounds 1018-1019

Scheme 7 illustrates the synthesis of compounds 1018-1019. Known aryliodide 83 was coupled to 4-hydroxymethylboronic acid to afford biarylalcohol 84. Alcohol 84 was converted to azide 85, which was used inalkyne cycloaddition reactions to afford triazoles 1018 and 1019.

Synthesis of Azide 85

Known aryl iodide 83 (Gravestock, M. B., International PatentApplication WO9910342) (1.00 g, 2.52 mmol) was dissolved in 6 mL DMF.4-Hydroxymethyl-phenylboronic acid (0.461 g, 3.03 mmol) was added,followed by potassium phosphate (K₃PO₄, 0.804 g, 3.79 mmol) andPd(PPh₃)₄ (0.292 g, 0.253 mmol). The mixture was degassed by evacuatingthe air from the flask, and refilling with argon (3 times), and thenheated to 100° C. for 4 hours. The mixture was allowed to cool and wasthen partitioned between ethyl acetate and water. The aqueous phase wasextracted with ethyl acetate, and the combined organic phase was washedwith brine, dried over MgSO₄, and evaporated. The residue waschromatographed on silica using a gradient mixture of methanol/methylenechloride (1% to 8%) to afford alcohol 84 (0.315 g, 0.838 mmol; 33%) asan ivory solid. An analytical sample was obtained by recrystallizing thematerial from methanol/methylene chloride/pentane. LCMS (ESI) m/z 377.

Alcohol 84 (0.889 g, 2.36 mmol) was suspended in 0.3 mL methylenechloride and 0.3 mL DMF. Triethylamine (0.66 mL, 4.74 mmol) was added,and the mixture was cooled to 0° C. Methanesulfonyl chloride (0.260 mL,3.36 mmol) was added dropwise, and the mixture was stirred for 25minutes. The mixture was then partitioned with ethyl acetate and water,and the organic layer was washed with brine, dried over MgSO₄, andevaporated. The residue was dissolved in 3 mL DMF, and sodium azide(0.384 g, 5.91 mmol) was added. The mixture was heated to 70° C. for 4hours. The reaction mixture was partitioned with ethyl acetate andwater, and the organic layer was washed with brine, dried over MgSO₄,and evaporated. The residue was chromatographed on silica using agradient mixture of methanol/methylene chloride (1% to 4%) to affordazide 85 (0.480 g, 1.20 mmol; 51%) as a tan solid. LCMS (ESI) m/z 402.

Synthesis of Triazole 1018

Azide 85 (0.084 g, 0.209 mmol) was dissolved in 0.7 mL THF and propargylalcohol (25 μL, 0.400 mmol) was added, followed by Hunig's base (73 μL,0.400 mmol) and copper(I) iodide (0.040 g, 0.210 mmol). The mixture wasallowed to stir overnight at room temperature, and then was placed in a−20° C. freezer for 2 days. The mixture was then partitioned with ethylacetate and water, and the aqueous layer was extracted with ethylacetate and then 2% methanol/methylene chloride. The combined organiclayer was washed with brine, dried over MgSO₄ and evaporated. Theresidue was chromatographed on silica using a gradient mixture ofmethanol/methylene chloride (1% to 8%) to afford triazole 1018 (0.060 g,0.131 mmol; 63%) as an ivory solid. LCMS (ESI) m/z 458.

Synthesis of Triazole 1019

Azide 85 (0.135 g, 0.337 mmol) was dissolved in 1.5 mL THF anddimethyl-prop-2-ynyl-amine (72 μL, 0.674 mmol) was added, followed byi-Pr₂NEt (117 μL, 0.674 mmol) and copper(I)iodide (0.064 g, 0.337 mmol).The mixture was allowed to stir overnight at room temperature (thesolvents evaporated overnight with positive pressure from argon gas).The residue was suspended in ethyl acetate and methylene chloride andfiltered through celite. The pad of celite was washed with ethyl acetateand methylene chloride, and the combined organic washes were evaporated.The residue was chromatographed on silica using a gradient mixture ofmethanol/methylene chloride (0% to 14%) and the product obtained wastriturated with methylene chloride and pentane. The tan solid wascollected to afford triazole 1019 (0.072 g, 0.149 mmol; 44%). LCMS (ESI)m/z 485.

Example 8 Synthesis of Compounds 1020-1021

Scheme 8 illustrates the synthesis of compounds 1020-1021. Bromoketone86 was subjected to alkylation with thioureas 87a and 87b to affordthiazoles 88a and 88b respectively. Coupling of 88a and 88b withboronate 81 yielded thiazoles 1020 and 1021.

Synthesis of Thiazole 88a

Bromoketone 86 (0.29 g, 1.0 mmol) was dissolved in dioxane (10 mL).Thiourea 87a (0.19 g, 1.2 mmol) and potassium carbonate (0.28 g, 2 mmol)were added sequentially and the resulting slurry stirred at 50° C. for 4h. The mixture was cooled to room temperature, diluted with 100 mLCH₂Cl₂, and washed with sat. aq. NaHCO₃, and brine. The aqueous washeswere back-extracted with CH₂Cl₂ (2×50 mL). The combined organic extractswere dried over K₂CO₃, filtered and concentrated in vacuo to afford 88aas a yellow solid (0.32 g) which was used without further purification.LCMS (ESI) m/z 353 (M+H)⁺.

Synthesis of Thiazole 1020

The crude aryl bromide 88a obtained above (0.20 g, 0.56 mmol), boronateester 81 (0.25 g, 0.66 mmol), and K₂CO₃ (0.14 g, 1.0 mmol) were combinedwith a 1:1:1 mixture of toluene, ethanol and water (2 mL each). Theslurry was degassed by alternately applying high vacuum to the reactionmixture and flushing with dry argon. The reaction vessel was then sealedand heated in an 80° C. oil bath for 14 h. The reaction mixture wascooled to room temperature, diluted with 100 mL 9:1 CH₂Cl₂/MeOH, andwashed with water and brine (50 mL each). The aqueous washes wereback-extracted once with 50 mL 9:1 CH₂Cl₂/MeOH. The combined organicextracts were dried on K₂CO₃, filtered, and concentrated in vacuo toafford 0.48 g of a brown solid which was purified by silica gelchromatography (25 mm×6″ column eluted with 7:3 acetone/hexane) to yield1020 as an off-white solid (0.17 g, 0.32 mmol). LCMS (ESI) m/z 525(M+H)⁺.

Synthesis of Thiazole 1021

Compound 21 was synthesized according to the procedure described abovefor 1020, using thiourea 88b in place of 88a. The reaction yielded 1021as a white solid (0.12 g, 0.21 mmol). LCMS (ESI) m/z 561 (M+H)⁺.

Example 9 Synthesis of Compounds 1022-1025

Scheme 9 illustrates the synthesis of compounds 1022-1025. Azetidine 89was deprotected and alkylated with chloride 90 to afford amide 91. Theamide of 91 was dehydrated with trifluoroacetic anhydride to producenitrile 1022. The alkylation of 1,2,3-triazole with benzyl chloride 90gave triazole 1023. Similarly, the alkylation of 5-aminotetrazole withbenzyl chloride 90 yielded a mixture of tetrazole 1024 and tetrazole1025.

Synthesis of Chloride 90

N-[3-(2-fluoro-4′-hydroxymethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide51 (3.0 g, 8.4 mmol) 51 was dissolved in CH₂Cl₂ (20 mL) and Hunig's base(2 mL). Methanesulfonyl chloride (1.4 mL, 12.6 mmol) was added dropwiseand the resulting solution stirred at room temperature for 4 h. Themixture was poured into 100 mL sat. aqueous NaHCO₃ and extracted withCH₂Cl₂ (3×50 mL). The combined organic extracts were washed with brine,dried over MgSO₄, filtered, and concentrated to give 3.9 g of an oilyyellow solid. The crude material was purified by silica gelchromatography to give chloride 90 as an off-white solid (2.7 g, 7.2mmol). LCMS (ESI) m/z 377 (M+H)⁺, 418 (M+CH₃CN+H)⁺, 440 (M+CH₃CN+Na)⁺.

Synthesis of Amide 91

A solution of 89 (J. Med. Chem. 1993, 36, 801) (33 mg, 0.17 mmol) inCH₂Cl₂ (1.0 mL) was treated with 4.0 M HCl-dioxane (0.2 mL) and stirredat 23° C. for 2 h. The reaction mixture was evaporated and the residuedissolved in DMF (1.0 mL) and treated with benzyl chloride 90 (63 mg,0.17 mmol) and Hunig's base (0.17 mL, 1.0 mmol) and stirred at 60° C.for 2 h. The reaction mixture was cooled to 23° C., diluted with H₂O (10mL) and extracted with CH₂Cl₂ (4×25 mL), dried (Na₂SO₄) and evaporated.The crude residue was purified by preparative TLC (1% NH₄OH-10% MeOH-89%CH₂Cl₂) to afford 91 (36 mg; 50%) as a tan powder. LCMS (ESI) m/z 441.1(M+H)⁺.

Synthesis of Nitrile 1022

A solution of 91 (26 mg, 0.06 mmol) in CH₂Cl₂ (1.0 mL) was treated withpyridine (0.02 mL, 0.2 mmol) and trifluoroacetic anhydride (0.035 mL,0.21 mmol) and stirred at 0° C. for 1 h. The reaction mixture wasdirectly purified by preparative TLC (1% NH₄OH-10% MeOH-89% CH₂Cl₂) toafford 1022 (6.0 mg; 24%) as a tan powder. LCMS (ESI) m/z 423.1 (M+H)⁺.

Synthesis of Triazole 1023

A solution of 90 (0.19 g, 0.50 mmol) in DMF (2.0 mL) was treated with1,2,3-triazole (0.058 mL, 1.0 mmol) and cesium carbonate (Cs₂CO₃, 0.33g, 1.0 mmol) and stirred at 23° C. for 16 h. The reaction mixture wasdiluted with H₂O (100 mL) and the resulting precipitate was isolated byfiltration and purified by preparative TLC (10% MeOH-45% CH₂Cl₂-45%EtOAc) to afford 1023 (39 mg; 19%) as a white powder. LCMS (ESI) m/z473.2 (M+CH₃CN+Na)⁺.

Synthesis of Tetrazoles 1024 and 1025

A solution of 90 (0.19 g, 0.50 mmol) in DMF (2.0 mL) was treated with5-aminotetrazole (87 mg, 1.0 mmol) and Cs₂CO₃ (0.33 g, 1.0 mmol) andstirred at 23° C. for 12 h. The reaction mixture was diluted with H₂O(100 mL) and the resulting precipitate was isolated by filtration andsuspended in 50 mL of a 1:1 mixture of CH₂Cl₂ and MeOH. The insolublematerial (55 mg; 26%) was isolated by filtration and assigned thestructure of 1024. LCMS (ESI) m/z 426.1 (M+H)⁺. The soluble material wasisolated by evaporation and purified by preparative TLC (1% NH₄OH-10%MeOH-89% CH₂Cl₂) to afford a white powder assigned the structure of 1025(39 mg; 19%). LCMS (ESI) m/z 489.2 (M+CH₃CN+Na)⁺.

Example 10 Synthesis of Compounds 1026 and 1027

Scheme 10 illustrates the synthesis of compounds 1026 and 1027. Azide 53was converted to triazole 1026, which was then subsequently cyclized tocompound 1027.

Synthesis of Triazole 1026

A solution of azide 53 (383 mg, 1.0 mmol) in ethanol (4.0 mL) wastreated with cyanoacetamide (101 mg, 1.2 mmol) and a solution of sodiumethoxide (21% wt solution in ethanol, 648 mg, 0.75 mL) at roomtemperature under N₂. The resulting reaction mixture was stirred for 10min at room temperature before being warmed up to reflux for 2 h. WhenTLC showed that the reaction was complete, the reaction mixture wascooled down to room temperature before being treated with H₂O (10 mL).The white precipitate was then collected by filtration, washed with H₂O(2×10 mL), and dried in vacuo to afford the desired triazole 1026 (312mg; 67%) as an off-white powder, which was of sufficient purity to beused directly in subsequent reactions. LCMS (ESI) m/z 468 (M+H).

Synthesis of Compound 1027

A suspension of 1026 (165 mg, 0.353 mmol) in anhydrous THF (5 mL) wastreated with p-toluenesulfonic acid monohydrate (34.2 mg, 0.18 mmol) andtrimethyl orthoformate (374 mg, 0.386 mL, 3.53 mmol) at 25° C. under N₂,and the resulting mixture was warmed up to reflux for 2 h. The solventswere removed in vacuo, and the residue was directly purified by columnchromatography (5-10% MeOH/CH₂Cl₂ gradient elution) to afford thedesired compound 1027 (42 mg; 25%) as a white powder. LCMS (ESI) m/z 478(M+H)⁺.

Example 11 Synthesis of Triazole 1028

A suspension of azide 53 (124 mg, 0.324 mmol) in anhydrous 1,4-dioxane(5.0 mL) was treated with propargyl alcohol (182 mg, 0.19 mL, 3.24 mmol)at 25° C., and the resulting reaction mixture was warmed up to refluxfor 12 h. When TLC and LCMS showed the reaction was complete, thereaction mixture was concentrated in vacuo, and the residue was directlypurified by column chromatography (0-5% MeOH/CH₂Cl₂ gradient elution) toafford triazole 1028 (93.9 mg; 66%) as a pale-yellow solid. LCMS (ESI)m/z 440 (M+H)⁺.

Example 12 Synthesis of Piperazine 1029 and Piperidine 1030

Scheme 11 illustrates the reductive amination chemistry used tosynthesize 1029 and 1030.

Synthesis of Piperazine 1029

A solution of aldehyde 92 (made from iodide 50 and 4-formylboronic acidin the same fashion asN-[3-(2-fluoro-4′-hydroxymethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamidein Example 1) (180 mg, 0.5 mmol) and 2-piperidin-4-yl-ethanol (65 mg,0.065 mL, 0.5 mmol) in anhydrous THF (4.0 mL) and anhydrous DMF (1.0 mL)was treated with sodium triacetoxyborohydride (160 mg, 0.75 mmol) at 25°C., and the resulting mixture was stirred at 25° C. for 12 h. When TLCand LCMS showed the reductive amination reaction was complete, thereaction mixture was concentrated in vacuo. The residue was directlypurified by flash column chromatography (0-5% MeOH—CH₂Cl₂ gradientelution) to afford piperazine 1029 (306 mg; 65%) as a colorless oil,which solidified upon standing at room temperature in vacuo. LCMS (ESI)m/z 471 (M+H)⁺.

Synthesis of Piperidine 1030

A solution of aldehyde 92 (356 mg, 1.0 mmol) and2-piperazin-1-yl-ethanol (130 mg, 0.123 mL, 1.0 mmol) in anhydrous THF(8.0 mL) and anhydrous DMF (1.6 mL) was treated with sodiumtriacetoxyborohydride (NaB(OAc)₃H, 318 mg, 1.5 mmol) at 25° C., and theresulting mixture was stirred at 25° C. for 12 h. When TLC and LCMSshowed the reductive amination reaction was complete, the reactionmixture was concentrated in vacuo. The residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford piperidine 1030 (169 mg; 72%) as a colorless oil, whichsolidified upon standing at room temperature in vacuo. LCMS (ESI) m/z470 (M+H)⁺.

Example 13 Synthesis of Imidazole 1031

Scheme 12 depicts the synthesis of tetrazole derivative 1031.D-p-Hydroxyphenyl-glycine was converted to triflate 95, which wassubsequently coupled to boronate 81 to afford alcohol 96. Mesylation of96, followed by displacement with the anion of imidazole anddeprotection of the BOC group yielded imidazole derivative 1031.

Synthesis of Triflate 95

A solution of D-p-hydroxyphenylglycine (23.8 g, 142.3 mmol) andpotassium carbonate (39.3 g, 284.6 mmol) in THF (200 mL) and H₂O (200mL) was treated with di-tert-butyl dicarbonate (BOC₂O, 34.14 g, 156.6mmol) at 25° C., and the resulting reaction mixture was stirred at 25°C. for 2 h. When TLC and LCMS showed that the reaction was complete, thereaction mixture was treated with ethyl acetate (200 mL) and H₂O (200mL). The two layers were separated, and the aqueous solution wasextracted with ethyl acetate (200 mL), and the combined organic extractswere discarded. The aqueous layer was then acidified with a 2 N HClaqueous solution to pH 4 before being extracted with ethyl acetate(2×200 mL). The combined organic extracts were then washed with water(2×100 mL) and saturated aqueous NaCl solution (100 mL), dried overMgSO₄, and concentrated in vacuo. The residual white solids were furtherdried in vacuo to afford the crude desired acid 93 (36.5 g; 96%), whichwas of suitable purity for use in subsequent reactions.

A solution of acid 93 (4.005 g, 15 mmol) in anhydrous THF (20 mL) wastreated dropwise with a 1 M solution of BH₃-THF in THF (30 mL, 30 mmol)at 0-5° C., and the resulting reaction mixture was stirred at 0-5° C.for an additional 2 h. When TLC and LCMS showed that the reductionreaction was complete, the reaction mixture was treated with water (50mL) and ethyl acetate (50 mL). The mixture was then stirred at 25° C.for 30 min before being separated, and the aqueous layer was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were thenwashed with water (2×20 mL) and saturated aqueous NaCl solution (20 mL),dried over MgSO₄, and concentrated in vacuo. The residue was thendirectly purified by flash column chromatography (0-5% MeOH—CH₂Cl₂gradient elution) to afford desired alcohol 94 (2.50 g; 66%) as a whitepowder which was of suitable purity for use in subsequent reactions.

A suspension alcohol 94 (670 mg, 2.65 mmol) in CH₂Cl₂ (10 mL) wastreated with N-phenyltrifluoromethane sulfonamide (947 mg, 2.65 mmol)and triethylamine (535.3 mg, 0.74 mL, 5.3 mmol) at 25° C., and theresulting reaction mixture was stirred at 25° C. for an additional 2 h.When TLC and LCMS showed that the reaction was complete, the reactionmixture was quenched with water (10 mL) and CH₂Cl₂ (20 mL). The twolayers were then separated, and the aqueous layer was extracted withCH₂Cl₂ (2×20 mL). The combined organic extracts were then washed withwater (2×10 mL) and saturated aqueous NaCl solution (10 mL), dried overMgSO₄, and concentrated in vacuo. The residue was then directly purifiedby flash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford triflate 95 (945 mg; 93%) as a white powder which was of suitablepurity for use in subsequent reactions.

Synthesis of Alcohol 96

A solution of boronate 81 (2.162 g, 5.72 mmol) and triflate 95 (1.70 g,4.4 mmol) in toluene (24 mL) was treated with solid potassium carbonate(1.82 g, 13.2 mmol), ethanol (8.0 mL) and H₂O (8.0 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(184 mg, 0.22 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed up to reflux for 2 h. When TLC and LCMS showed that the reactionwas complete, the reaction mixture was cooled down to room temperaturebefore being treated with water (20 mL) and ethyl acetate (20 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (2×20 mL). The combined organic extracts were washed withwater (2×20 mL) and saturated aqueous NaCl solution (20 mL), dried overMgSO₄, and concentrated in vacuo. The residue was then purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford(1-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-2-hydroxyethyl)carbamicacid tert-butyl ester 96 (1.543 g; 72%) as yellow oil, which solidifiedupon standing at room temperature in vacuo.

Synthesis of Mesylate 97

A suspension of alcohol 96 (694 mg, 1.43 mmol) in anhydrous CH₂Cl₂ (10mL) was treated with diisopropylethylamine (388 mg, 0.522 mL, 2.85 mmol)and methanesulfonyl chloride (196 mg, 0.132 mL, 1.71 mmol) at 0-5° C.,and the resulting reaction mixture was stirred at 0-5° C. for anadditional 2 h. When TLC and LCMS showed that the reaction was complete,the reaction mixture was quenched with water (10 mL). The two layerswere separated, and the aqueous layer was extracted with CH₂Cl₂ (2×10mL). The combined organic extracts were washed with water (2×10 mL) andsaturated aqueous NaCl solution (10 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was then purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford mesylate 97(647 mg; 80%) as a pale-yellow solid, which was of suitable purity foruse in subsequent reactions.

Synthesis of Imidazole 98

A solution of imidazole (41 mg, 0.6 mmol) in anhydrous THF (3 mL) wastreated with NaH (60% oil dispersion, 29 mg, 0.72 mmol) at 0° C., andthe resulting mixture was stirred at 0-5° C. for 30 min before asolution of mesylate 97 (170 mg, 0.3 mmol) in anhydrous DMF (3.0 mL) wasadded. The resulting reaction mixture was then stirred at 0-5° C. for 30min before being gradually warmed up to room temperature for 12 h. WhenTLC and LCMS showed that the reaction was complete, the solvents wereremoved in vacuo, and the residue was directly purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford imidazole98 (46 mg; 29%) as a yellow solid.

Synthesis of Imidazole 1031

A solution of imidazole 98 (23 mg, 0.043 mmol) in MeOH (1.0 mL) wastreated with a solution of 4 N HCl in 1,4-dioxane (3.0 mL), and theresulting reaction mixture was stirred at room temperature for 30 min.When TLC and LCMS showed that the reaction was complete, the solventswere removed in vacuo, and the desiredN-{3-[4′-(1-amino-2-imidazol-1-yl-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}acetamidehydrochloride 1031 (18.8 mg; 100%) was obtained as a yellow solid. LCMS(ESI) m/z 438 (M+H)⁺.

Example 14 Synthesis of tetrazoles 1032-1034

Scheme 13 depicts the synthesis of tetrazole derivatives 1032-1034.Iodide 99 was converted to boronate 100 which served as the couplingpartner for bromide 101 to afford tetrazole 102. Deprotection of 102afforded tetrazole amine 1032, which was subsequently acylated to affordtetrazole 1033 and 1034.

Synthesis of Iodide 99

A solution of known5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (2.02 g, 6.0mmol; see U.S. Pat. Nos. 5,523,403 and 5,565,571) and potassiumcarbonate (1.66 g, 12.0 mmol) in THF (20 mL) and H₂O (20 mL) was treatedwith BOC₂O (1.334 g, 6.12 mmol) at 25° C., and the resulting reactionmixture was stirred at 25° C. for 2 h. When TLC and LCMS showed thereaction was complete, the reaction mixture was treated with ethylacetate (20 mL) and H₂O (20 mL). The two layers were separated, and theaqueous solution was extracted with ethyl acetate (20 mL), and thecombined organic extracts were then washed with water (2×10 mL) andsaturated aqueous NaCl solution (10 mL), dried over MgSO₄, andconcentrated in vacuo. The residual white solids were further dried invacuo to afford the crude, desired iodide 99 (2.40 g; 92%), which was ofsuitable purity for use in subsequent reactions.

Synthesis of Boronate 100

A solution of iodide 99 (1.11 g, 2.55 mmol) in 1,4-dioxane (25 mL) wastreated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (489 mg, 0.56 mL,3.82 mmol) and triethylamine (772 mg, 1.07 mL, 7.65 mmol) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(107 mg, 0.13 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed up to reflux for 6 h. When TLC and LCMS showed that the reactionwas complete, the reaction mixture was cooled down to room temperaturebefore being treated with water (20 mL) and ethyl acetate (20 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (2×20 mL). The combined organic extracts were washed withwater (2×20 mL) and saturated aqueous NaCl solution (20 mL), dried overMgSO₄, and concentrated in vacuo. The residual brown oil was thenpurified by flash column chromatography (10-30% EtOAc-hexanes gradientelution) to afford boronate 100 (646 mg; 58%) as a brown oil, whichsolidified upon standing at room temperature in vacuo and was ofsuitable purity for use in subsequent reactions.

Synthesis of Bromide 101

A solution of 4-bromobenzylamine hydrochloride (2.22 g, 10.0 mmol) inacetic acid (30 mL) was treated with triethyl orthoformate (2.964 g,3.29 mL, 20.0 mmol) and sodium azide (2.30 g, 20.0 mmol) at roomtemperature, and the resulting reaction mixture was subsequently stirredat reflux for 12 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was cooled down to room temperature, andthe cooled reaction mixture was poured into ice-water (100 mL). Theprecipitate was then collected by filtration, washed with water (2×20mL), and dried in vacuo to afford crude bromide 101 (460 mg; 19%) as awhite solid, which was of suitable purity for use in subsequentreactions.

Synthesis of Tetrazole 102

A solution of boronate 100 (658 mg, 1.5 mmol) and bromide 101 (300 mg,1.25 mmol) in toluene (9.0 mL) was treated with solid potassiumcarbonate (621 mg, 4.5 mmol), ethanol (3.0 mL) and H₂O (3.0 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(52.3 mg, 0.063 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed up to reflux for 3 h. When TLC and LCMS showed that the reactionwas complete, the reaction mixture was cooled down to room temperaturebefore being treated with water (10 mL) and ethyl acetate (20 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic extracts were washed withwater (2×5 mL) and saturated aqueous NaCl solution (5 mL), dried overMgSO₄, and concentrated in vacuo. The residue was then purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordtetrazole 102 (357 mg; 61%) as a yellow oil, which solidified uponstanding at room temperature in vacuo.

Synthesis of Tetrazole 1032

A solution of tetrazole 102 (350 mg, 0.748 mmol) in EtOAc (5.0 mL) wastreated with a solution of 4 N HCl in 1,4-dioxane (5.0 mL), and theresulting reaction mixture was stirred at room temperature for 30 min.When TLC and LCMS showed that the reaction was complete, the solventswere removed in vacuo, and the residue was treated with an aqueoussodium bicarbonate solution (10 mL) and EtOAc (15 mL). The mixture wasstirred at room temperature for 30 min before the two layers wereseparated. The aqueous layer was extracted with EtOAc (10 mL), and thecombined organic extracts were washed with H₂O (10 mL) and saturatedaqueous NaCl solution (10 mL), dried over MgSO₄, and concentrated invacuo to afford tetrazole amine 1032 (266 mg; 97%) as a pale-yellowsolid. LCMS (ESI) m/z 369 (M+H)⁺.

Synthesis of Tetrazole 1033

A suspension of tetrazole amine 1032 (74 mg, 0.2 mmol) in anhydrousCH₂Cl₂ (5.0 mL) was treated with diisopropylethylamine (52 mg, 0.07 mL,0.4 mmol) and chloroacetyl chloride (34 mg, 0.024 mL, 0.3 mmol) at 0-5°C., and the resulting reaction mixture was stirred at 0-5° C. for 2 h.When TLC and LCMS showed the reaction was complete, the reaction mixturewas concentrated in vacuo. The residue was directly purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordtetrazole 1033 (43 mg; 48% yield) as a white solid. LCMS (ESI) m/z 445(M+H)⁺.

Synthesis of Tetrazole 1034

A suspension of tetrazole amine 1032 (74 mg, 0.2 mmol) in anhydrousCH₂Cl₂ (5.0 mL) was treated with diisopropylethylamine (52 mg, 0.07 mL,0.4 mmol) and dichloroacetyl chloride (44 mg, 0.029 mL, 0.3 mmol) at0-5° C., and the resulting reaction mixture was stirred at 0-5° C. for 2h. When TLC and LCMS showed the reaction was complete, the reactionmixture was concentrated in vacuo. The residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford tetrazole 1034 (41 mg; 43% yield) as a white solid. LCMS (ESI)m/z 479 (M+H)⁺.

Example 15 Synthesis of Compounds 1035 and 1036

Scheme 14 depicts the synthesis of tetrazole derivatives 1035 and 1036.Aldehyde 103 was reduced to 104 which was coupled to boronate 81 toyield alcohol 105. Mesylation of 105, followed by displacement withsodium azide, yielded azide 107. Reduction of 107 to amine 108 wasfollowed by conversion to tetrazole 1035. Cycloaddition of azide 107with trimethylsilylacetylene, followed by desilylation, affordedtriazole 1036.

Synthesis of Aldehyde 103

A solution of 2,5-dibromopyridine (25 g, 105.5 mmol) in toluene (1.24 L)was cooled down to −78° C. before being treated dropwise with a 2.5 Msolution of n-BuLi in hexane (50.6 mL, 126.6 mmol) at −78° C. under N₂.The resulting reaction mixture was stirred at −78° C. for 1 h beforebeing treated with anhydrous DMF (11.6 g, 12.2 mL, 158.0 mmol) at −78°C. The reaction mixture was stirred at −78° C. for an additional 1 hbefore being gradually warmed up to room temperature for 6 h. When TLCand LCMS showed that the reaction was complete, the reaction mixture wasquenched with water (200 mL). The two layers were separated, and theaqueous layer was extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were then washed with H₂O (2×200 mL), and saturatedaqueous NaCl solution (100 mL), and dried over MgSO₄. The solvents werethen removed in vacuo, and the residual pale-yellow oil was purified byflash column chromatography (0-15% EtOAc-hexane gradient elution) toafford aldehyde 103 (10.2 g; 52%) as a pale-yellow solid.

Synthesis of Bromide 104

A solution aldehyde 103 (4.91 g, 26.4 mmol) in methanol (120 mL) wastreated with sodium borohydride (1.18 g, 31.7 mmol) at 0-5° C., and theresulting reaction mixture was stirred at 0-5° C. for an additional 1 h.When TLC and LCMS showed that the reaction was complete, the reactionmixture was quenched with water (20 mL). The solvents were then removedin vacuo, and the residue was directly purified by flash columnchromatography (5-25% EtOAc-hexane gradient elution) to afford bromide104 (4.23 g; 85%) as a white solid.

Synthesis of Alcohol 105

A solution of boronate 81 (11.05 g, 29.2 mmol) and bromide 104 (4.227 g,22.5 mmol) in toluene (150 mL) was treated with solid potassiumcarbonate (9.315 g, 67.5 mmol), ethanol (50 mL) and H₂O (50 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(564 mg, 0.675) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed up to reflux for 1 h. When LCMS showed that the reaction wascomplete, the reaction mixture was cooled down to room temperaturebefore being treated with water (200 mL) and ethyl acetate (100 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (2×50 mL). The combined organic extracts were washed withwater (2×50 mL) and saturated aqueous NaCl solution (50 mL), dried overMgSO₄, and concentrated in vacuo. The residue was then purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordalcohol 105 (6.16 g; 76%) as a grey solid.

Synthesis of Azide 107

A suspension of alcohol 105 (2.15 g, 6.0 mmol) in CH₂Cl₂ (25 mL) wastreated with diisopropylethylamine (1.551 g, 2.10 mL, 12.0 mmol) andmethanesulfonyl chloride (756 mg, 0.511 mL, 6.6 mmol) at 0-5° C., andthe resulting reaction mixture was stirred at 0-5° C. for an additional2 h. When TLC and LCMS showed that the reaction was complete, thereaction mixture was treated with water (20 mL) and CH₂Cl₂ (40 mL). Thetwo layers were separated, and the aqueous layer was extracted withCH₂Cl₂ (20 mL). The combined organic extracts were washed with water (20mL) and saturated aqueous NaCl solution (20 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was then purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford mesylate106 (2.47 g; 94%) as a yellow solid.

A solution of mesylate 106 (874 mg, 2.0 mmol) in DMF (8.0 mL) wastreated with sodium azide (260 mg, 4.0 mmol) at room temperature, andthe resulting reaction mixture was warmed up to 40-45° C. for 3 h. WhenTLC and LCMS showed that the reaction was complete, the reaction mixturewas treated with water (20 mL), and the precipitate was collected byfiltration, washed with water (2×10 mL), and dried in vacuo to affordcrude azide 107 (699 mg; 91%) as a grey solid, which was of suitablepurity for use in subsequent reactions.

Synthesis of Amine 108

A suspension of azide 107 (2.611 g, 6.8 mmol) in THF (25 mL) was treatedwith water (0.13 mL, 68 mmol) and triphenylphosphine (PPh₃, 2.14 g, 8.2mmol) at room temperature, and the resulting reaction mixture wassubsequently stirred at room temperature for 12 h. When TLC and LCMSshowed that the reaction was complete, the solvents were removed invacuo, and the residue was directly purified by flash columnchromatography (0-15% MeOH—CH₂Cl₂ gradient elution) to afford amine 108(2.233 g; 92%) as a yellow solid.

Synthesis of Tetrazole 1035

A solution of amine 108 (90 mg, 0.25 mmol) in acetic acid (3.0 mL) wastreated with triethyl orthoformate (0.1 mL) and sodium azide (40 mg) atroom temperature, and the resulting reaction was subsequently stirred atreflux for 4 h. When TLC and LCMS showed that the reaction was complete,the reaction mixture was cooled down to room temperature andconcentrated in vacuo. The residue was then directly purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordtetrazole 1035 (43 mg; 36%) as a white solid. LCMS (ESI) m/z 412 (M+H)⁺.

Synthesis of Triazole 1036

A solution of azide 107 (142 mg, 0.37 mmol) in DMF (5 mL) was treatedwith thimethylsilyl acetylene (0.5 mL) at room temperature, and theresulting reaction mixture was subsequently stirred at 70-80° C. for 12h. When TLC and LCMS showed that the reaction was complete, the reactionmixture was cooled down to room temperature before being concentrated invacuo. The residue was then directly purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford triazole109 (152 mg; 85%) as a pale-yellow oil, which was directly used in thesubsequent reaction.

A solution of triazole 109 (152 mg, 0.315 mmol) in THF (10 mL) wastreated with a 1N solution of tetrabutylammonium fluoride in THF (2.0mL) at 0-5° C., and the resulting reaction mixture was stirred at 0-5°C. for 1 h before being gradually warmed up to room temperature for 10h. When TLC and LCMS showed that the reaction was complete, the reactionmixture was cooled down to room temperature before being concentrated invacuo. The residue was then directly purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford triazole1036 (67 mg; 52%) as a pale-yellow oil, which solidified upon standingat room temperature in vacuo. LCMS (ESI) m/z 411 (M+H)⁺.

Example 16 Synthesis of Triazole 1037

A solution of mesylate 52 (436 mg, 1.0 mmol) in anhydrous DMF (5 mL) wastreated with 1,2,4-triazole sodium salt (182 mg, 2.0 mmol) at 0-5° C.,and the resulting reaction mixture was stirred at 0-5° C. for 1 h beforebeing gradually warmed up to room temperature for 10 h. When TLC andLCMS showed that the reaction was complete, the reaction mixture wasconcentrated in vacuo. The residue was then directly purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordtriazole 1037 (388 mg; 95%) as a white solid. LCMS (ESI) m/z 410 (M+H)⁺.

Example 17 Synthesis of Piperazine 1038

A suspension of the aldehyde 92 (142 mg, 0.4 mmol) in MeOH (4.0 mL) andTHF (1.0 mL) was treated with1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)piperazine (106 mg, 0.4 mmol)and sodium triacetoxyborohydride (160 mg, 0.8 mmol) at 25° C., and theresulting reaction mixture was stirred at 25° C. for 6 h. When TLC andLCMS showed the reductive amination reaction was complete, the reactionmixture was concentrated in vacuo. The residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford piperazine 1038 (38 mg; 16% yield) as a colorless oil, whichsolidified upon standing at room temperature in vacuo. LCMS (ESI) m/z607 (M+H)⁺.

Example 18 Synthesis of Tetrazoles 1039-1042

Scheme 15 shows the synthesis of compounds 1039-1042. Nitrile 110 isconverted to tetrazole 1039, which was deprotected to afford tetrazole1040. Tetrazole 1039 is methylated to afford 1041, which wassubsequently deprotected to yield 1042.

Synthesis of Nitrile 110

A suspension of aldehyde 92 (1.884 g, 5.3 mmol) in MeOH (25 mL) wastreated with a solution of NaCN (312 mg, 6.4 mmol) in H₂O (10 mL) and asolution of ammonium chloride (340 mg, 6.4 mmol) in H₂O (15 mL) at 25°C., and the resulting mixture was stirred at 25° C. for 30 min beforebeing warmed up to 50° C. for 1 h. When TLC and LCMS showed that thereaction was complete, the reaction mixture was cooled down to roomtemperature before being treated with H₂O (25 mL) at 25° C., and theresulting mixture was cooled down to 0-5° C. for 1 h. The solidprecipitates were collected by filtration, washed with H₂O (2×20 mL) and20% EtOAc/hexane (2×20 mL), and dried in vacuo. The crude desiredN-{3-[4′-(amino-cyano-methyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide(1.801 g; 89% yield) was obtained as off-white solids, which by HPLC and¹H NMR was of sufficient purity to be used in subsequent reactions. LCMS(ESI) m/z 383 (M+H)⁺.

A solution ofN-{3-[4′-(amino-cyano-methyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamideobtained above (1.70 g, 4.45 mmol) in THF (40 mL) and H₂O (40 mL) wastreated with benzyl chloroformate (940 mg, 5.34 mmol) and potassiumcarbonate (1.23 g, 8.9 mmol) at 25° C., and the resulting reactionmixture was stirred at 25° C. for 2 h. When TLC and LCMS showed thereaction was complete, the reaction mixture was quenched with H₂O (20mL) and EtOAc (50 mL). The two layers were separated, and the aqueouslayer was extracted with EtOAc (50 mL). The combined organic extractswere washed with water (2×20 mL), and saturated aqueous NaCl solution(20 mL), dried over MgSO₄, and concentrated in vacuo. The residue wasthen purified by column chromatography (0-5% MeOH—CH₂Cl₂ gradientelution) to afford the desired nitrile 110 (2.20 g; 96%) as a colorlessoil, which solidified upon standing at room temperature in vacuo. Thismaterial by ¹H NMR was found to be a mixture of two diastereomers. LCMS(ESI) m/z 517 (M+H)⁺.

Synthesis of Tetrazole 1039

A solution of 0.130 g (2.52 mmol) of nitrile 110, 0.033 g (5.04 mmol) ofNaN₃, and 0.028 g (1.26 mmol) of zinc bromide (ZnBr₂) in 9 ml ofisopropanol/H₂O (1:2) was allowed to stir at reflux for 24 h. Once thereaction mixture cooled down, it was diluted with 1 N HCl, extractedwith MeOH/CH₂Cl₂ (1:3) (40 ml×3), and the combined organic layers werewashed with brine, dried over MgSO₄, and evaporated to give 0.050 g oftetrazole 1039 as a mixture of tautomers. LCMS (ESI) m/z 560 (M+H)⁺.

Synthesis of Tetrazole 1040

A solution of 0.030 g of 1039 and 0.020 g of palladium on carbon (Pd/C)(10%) in 6 ml of (1:1 H₂O/THF) was allowed to stir at 25° C. under H₂atmosphere (balloon) for 16 h. The reaction mixture was filtered throughcelite, and washed with MeOH/CH₂Cl₂. The filtrate was concentrated,washed with small amount of EtOAc, then dried via vacuum to give 0.010 gof tetrazole 1040. LCMS (ESI) m/z 426 (M+H)⁺.

Synthesis of Methyl Tetrazole 1041

A solution of 0.218 g (0.39 mmol) of 1039, 0.080 g (0.58 mmol) of K₂CO₃,and 0.061 g (0.43 mmol) of methyl iodide (MeI) in 5 ml of DMF wasallowed to stir at 25° C. for 16 h. The reaction solvent was removed byvacuum. The residue was dissolved in a mixture of MeOH/CH₂Cl₂ (1:1),filtered through a pipette column, and the filtrate was concentrated togive the crude product 1041 in the amount of about 0.220 g. A smallamount was purified through preparative HPLC. LCMS (ESI) m/z 574 (M+H)⁺.

Synthesis of Methyl Tetrazole 1042

A solution of 0.220 g of 1041 and 0.020 g of Pd (10% on carbon) in 3 mlof DMF was allowed to stir at 25° C. under H₂ atmosphere (balloon) for24 h. The solvents were removed by rotary evaporation, the residue wasthen dissolved in a mixture of MeOH/CH₂Cl₂, and filtered through celite.The filtrate was concentrated and further purified by preparative HPLCto give 0.052 g of methyl tetrazole 1042. LCMS (ESI) m/z 440 (M+H)⁺.

Example 19 Synthesis of Pyrazole 1043

To a suspension of 0.048 g (2.0 mmol) of NaH and 0.125 g (1.83 mmol) ofpyrazole in 8 ml of DMF at 0° C. was added 0.400 g (0.92 mmol) ofmesylate 52. Then, the reaction mixture was warmed up to 25° C., and wasallowed to stir for 3 h. The DMF was removed and the residue waspurified by preparative TLC to give 0.360 g of pyrazole 1043 (96%yield). LCMS (ESI) m/z 409 (M+H)⁺.

Example 20 Synthesis of Compounds 1044-1046

Scheme 16 depicts the synthesis of aryl bromides 112-114 required forthe synthesis of compounds 1044-1046. Epoxide 111 was treated with1-formyl piperazine to afford a mixture of 112 and 113. Epoxidering-opening of 111 with imidazole afforded 114. These bromides werecoupled with boronate 81 to deliver the target compounds 1044-1046.

Synthesis of epoxide 111

To a solution of 4-bromostyrene (5.00 g, 26.8 mmol) in CH₂Cl₂ (130 mL)was added 4-methylmorpholine N-oxide (NMO, 12.90 g, 107.1 mmol,anhydrous) and Jacobsen catalyst((1S,2S)-(+)-[1,2-(cyclohexanodiamino-N,N′-bis(3,5-di-t-butyl-salicylidene)]manganese(III)chloride, 850 mg, 1.34 mmol). The solution was cooled to −78° C., thenm-chloroperbenzoic acid (r-CPBA, 7.40 g, 42.8 mmol) was added in fourportions every 10 min. The mixture was stirred at −78° C. for 2 h. Thereaction was quenched by addition of sodium thiosulfate (Na₂S₂O₃)solution (10.0 g in 30 mL water), then the cooling bath was removed, andwater (70 mL), 1N sodium hydroxide (NaOH, 60 mL) was added. The aqueousphase was extracted with CH₂Cl₂ (30 mL×3), dried with Na₂SO₄, andevaporated. The residue was purified by flash chromatography (4:100Et₂O/Hexane) to yield 5.20 g epoxide 111 (98% yield).

General Procedure for the Synthesis of Bromides 112-114 from Epoxide 111

To a suspension of epoxide 111 (1 mmol, 1 eq) in acetonitrile (3.0 mL)at room temperature was added lithium perchlorate (LiClO₄, 1.05 mmol,1.05 eq). After the formation of a clear solution, the amine (1.5 mmol,1.5 eq) was added. The mixture was stirred at room temperature or at 60°C. The solvent was removed under vacuum and the residue was purified byflash chromatography.

Conditions for 112 and 113: room temperature, 16 h, flash chromatography(3:100 MeOH/CH₂Cl₂). Yield of 112: 132 mg; Yield of 113: 42 mg.Conditions for 114: 60° C., 4 h, flash chromatography (3:100MeOH/CH₂Cl₂). Yield of 114: 103 mg.General Procedure for the Synthesis of Compounds 1044-1046 from Bromides112-114

A suspension of bromide intermediate (1 eq), boronate 81 (1 eq),PdCl₂(dppf)₂ (0.05 eq), and K₂CO₃ (4 eq) in a mixture ofdioxane/EtOH/H₂O (ratio of 3:1:1) was degassed by a stream of argon. Themixture was stirred at 75° C. to 85° C. for 3 to 15 h. The solvent wasremoved by vacuum and the residue was purified by flash chromatographyto afford the product.

Conditions for 1044: 80° C., 3.5 h, flash chromatography (4:100MeOH/CH₂Cl₂); Yield 150 mg. LCMS (ESI) m/z 485 (M+H)⁺.Conditions for 1045: 80° C., 3.5 h, flash chromatography (5:100MeOH/CH₂Cl₂); Yield 52 mg. LCMS (ESI) m/z 485 (M+H)⁺.Conditions for 1046: 80° C., 2.5 h, flash chromatography (10:100MeOH/CH₂Cl₂); Yield 155 mg. LCMS (ESI) m/z 439 (M+H)⁺.

Example 21 Synthesis of Compounds 1047 and 1048

Scheme 17 depicts the synthesis of tetrazoles 1047 and 1048. Azides 53and 85 were reduced to amines 115 and 116 respectively. These amineswere then converted to triazoles 1047 and 1048 by treatment with sodiumazide and trimethylorthoformate in hot acetic acid.

Synthesis of Amine 54

Amine 54 was prepared from azide 53 according to the method described inExample 1.

Synthesis of Amine 116

Azide 85 (1.10 g, 2.74 mmol) was dissolved in 17 mL THF and 0.6 mLwater. Triphenylphosphine (1.30 g, 4.96 mmol) was added, and the mixturewas heated to reflux for 4 h. The mixture was allowed to stir overnightat room temperature, and was partitioned between ethyl acetate and 20 mL2N aqueous HCl. The organic layer was extracted with 20 mL 2N aqueousHCl, and then the aqueous layer was basified with 85 mL 1N aqueous NaOH.The cloudy aqueous phase was extracted with ethyl acetate (2×), and 5%methanol/methylene chloride (2×). The combined organic extracts weredried over Na₂SO₄, and evaporated. The residue was chromatographed onsilica gel using a gradient elution of methylene chloride thenmethanol/methylene chloride (up to 10% methanol) to afford amine 116(0.587 g, 1.57 mmol; 57%) as a tan solid. LCMS (ESI) m/z 376 (M+H)⁺.

Synthesis of Tetrazole 1047

A solution of amine 54 (0.20 g, 0.56 mmol) in acetic acid (5 mL) wastreated with sodium azide (0.05 g, 0.84 mmol) followed bytriethylorthoformate (0.15 mL, 0.90 mmol).

The reaction mixture was heated to reflux for 4 h. The mixture wascooled and added to ice water (10 mL). After standing at roomtemperature for 48 h, the precipitated product was collected byfiltration and washed with cold CH₃OH to yield tetrazole 1047 (101 mg;50%) as a white solid. LCMS (ESI) m/z 474 (M+H)⁺.

Synthesis of Tetrazole 1048

Tetrazole 1048 was made from amine 116 using the same procedure for thesynthesis of 1047. LCMS (ESI) m/z 429.

Example 22 Synthesis of Compounds 1049-1054 Synthesis of 1049

A solution of mesylate 52 (0.10 g, 0.24 mmol) in dimethyl sulfoxide(DMSO, 2.0 mL) was treated with ethyl 4-pyrazole carboxylate (0.03 g,0.24 mmol), K₂CO₃ (0.06 g, 0.46 mmol) and the mixture was heated to 90°C. for 16 h. The reaction mixture was cooled to room temperature,diluted with ethyl acetate (100 mL), and washed with brine (2×50 mL).The organic phase was dried and evaporated. The residue was purified bypreparative thin layer chromatography (using 95% CH₂Cl₂, 5% MeOH aseluant) to provide 1049. LCMS (ESI) m/z 481 (M+H)⁺.

Synthesis of 1050

This compound was made from mesylate 52 and 4-(hydroxymethyl)imidazoleusing the same procedure described for the synthesis of 1049. LCMS (ESI)m/z 439 (M+H)⁺.

Synthesis of 1051

This compound was made from mesylate 52 and 4-pyrazolecarboxylic acidusing the same procedure described for the synthesis of 1049. LCMS (ESI)m/z 453 (M+H)⁺.

Synthesis of 1052

This compound was made from mesylate 52 and 4-methylpyrazole using thesame procedure described for the synthesis of 1049. LCMS (ESI) m/z 423(M+H)⁺.

Synthesis of 1053

This compound was made from mesylate 52 and 3-aminopyrazole using thesame procedure for the synthesis of 1049. LCMS (ESI) m/z 424 (M+H)⁺.

Synthesis of 1054

This compound was made from mesylate 52 and pyrrole using the sameprocedure for the synthesis of 1049. LCMS (ESI) m/z 408 (M+H)⁺.

Example 23 Synthesis of Aldehyde 1055

A solution of amine 54 (0.20 g, 0.56 mmol) in acetic acid (5 mL) wastreated with 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (0.12 g, 0.78mmol). The reaction mixture was heated to reflux for 2 h. The mixturewas cooled and the solvent removed under high vacuum. The residue waspurified by preparative thin layer chromatography (using 95% CH₂Cl₂, 5%MeOH as eluant) to provide 1055. LCMS (ESI) m/z 436 (M+H)⁺.

Example 24 Synthesis of Tetrazole 1056

A solution of mesylate 52 (0.50 g, 1.14 mmol) in acetonitrile (CH₃CN, 5mL) was treated with tetrazole (12 mL, 5.73 mmol), and triethylamine(0.8 mL, 5.73 mmol), and the mixture was heated to reflux for 18 h. Thereaction mixture was cooled to room temperature and diluted with ethylacetate (100 mL), and washed with brine (2×50 mL). The organic phase wasdried and evaporated. The residue was purified by preparative thin layerchromatography (using 95% CH₂Cl₂, 5% MeOH as eluant) to provide 1056.LCMS (ESI) m/z 411.

Example 25 Synthesis of Imidazole 1084

Scheme 18 depicts the synthesis of imidazole 1084.

Synthesis of iodide 120

To a suspension of alcohol 117 (5 g, 14.84 mmol) in CH₂Cl₂ (80 mL) wasadded triethyl amine (2.5 mL, 17.8 mmol) and methanesulphonyl acidchloride (1.4 mL, 17.8 mmol) at 0° C. and stirred the clear solution for1 h at the same temperature. The reaction mixture was poured into brinesolution (100 mL) and extracted with CH₂Cl₂ (2×50 mL). The combinedorganic layer was washed with brine solution (3×100 mL), dried overanhydrous Na₂SO₄, and concentrated to yield mesylate 118. To this wasadded NaN₃ (2 g, 29.7 mmol) and DMF (50 mL) and the mixture was heatedto 80° C. overnight. The solution was poured into a mixture of ethylacetate (150 mL) and water (100 mL). The organic layer was separated andthe aqueous portion was extracted with ethyl acetate (3×50 mL). Thecombined organic layer was washed with brine (1×150 mL), dried overanhydrous Na₂SO₄, and concentrated to yield 5.4 g of azide 119.

A solution of aizde 119 (5.4 g, 14.84 mmol) and trimethylsilyl acetylene(10.48 mL, 74.2 mmol) in DMF (20 mL) was heated to 90° C. for 12 h. Thereaction mixture was concentrated and treated with TBAF (60 mL, 1M inTHF) and acetic acid (2 mL, 29.7 mmol) and stirred at ambienttemperature for 12 h. The solution was concentrated and poured into amixture of saturated NH₄Cl (50 mL), ethyl acetate (150 mL) and brinesolution (50 mL). The organic layer was separated and the aqueousportion was extracted with ethyl acetate (3×50 mL). The combined organiclayer was dried over anhydrous Na₂SO₄, concentrated and the solid thusobtained was washed with water (5×200 mL) to yield 5.7 g of tetrazolederivative 120. LCMS (ESI) m/e 389 (M+H⁺).

Synthesis of Alcohol 122

To a mixture of tetrazole 120 (5.7 g, 14.84 mmol), boronic acid 121 (2.9g, 19.29 mmol), K₂CO₃ (6.0 g, 44.52 mmol) and Pd(PPh₃)₄ (857 mg, 5 mol%) was added toluene (120 mL), ethyl alcohol (40 mL) and water (40 mL).The reaction mixture was degassed, flushed with argon, and refluxed for4 h. The solvent was concentrated under reduced pressure and the residuethus obtained was poured into water (2000 mL). The pale yellow solid wasfiltered, and dried at 40° C. under vacuum to yield 4.76 g of alcohol122. LCMS (ESI) m/e 369 (M+H⁺).

Synthesis of Chloride 123

To a solution of alcohol 122 (4.6 g, 12.5 mmol) and Hunig's base (6.4mL, 38.75 mmol) in DMF (40 mL) and CH₂Cl₂ (30 mL) was addedmethanesulphonyl chloride (2.9 mL, 37.5 mmol) at 0° C., and theresulting solution was stirred at ambient temperature for 3 h. Thesolution was concentrated to remove the CH₂Cl₂ and poured into water(1000 mL). The pale yellow solid was filtered and successively washedwith water (5×200 mL), 10% ethyl acetate in hexanes (5×100 mL) and 50%ether in hexanes (5×100 mL). The resulting solid was dried at 40° C.under vacuum to yield 4.5 g of chloride 123. LCMS (ESI) m/e 387 (M+H⁺).

Synthesis of 1084

To a solution of imidazole (31 mg, 0.224 mmol) in DMF (3 mL) was addedNaH (17 mg, 0.448 mmol) at 0° C., and the solution was stirred for 20min at 0° C. Chloride 123 was added and the reaction was stirred atambient temperature for 90 min. The reaction mixture was concentratedand purified by flash chromatography over silica gel (96:4 CH₂Cl₂/MeOH)to yield 65 mg of 1084. LCMS (ESI) m/e 419 (M+H⁺).

Example 26 Synthesis of Imidazole 1086

Scheme 19 depicts the synthesis of imidazole 1086.

To a solution of imidazole 124 (0.25 g, 0.56 mmol) in dry CH₂Cl₂ (3 mL)was added 1-Methyl magnesium bromide (EtMgBr) in THF (0.62 mL, 0.62mmol) at room temperature. After stirring for 45 min, oxazolidinone 90(0.233 g, 0.62 mmol) was added to the mixture and stirring continuedovernight. The reaction was quenched with aqueous NH₄Cl (20 mL),extracted with CH₂Cl₂ (25 mL) and dried over Na₂SO₄. The solvent wasevaporated to yield 125 as a solid residue. The crude was dissolved in10% MeOH in CH₂Cl₂ (10 mL), and 1N HCl in diethyl ether (2 mL, 2 mmol)was added, followed by stirring for 3 h. The solvent was evaporated andthe residue was partitioned between dilute NH₄OH (30 mL) and CH₂Cl₂ (30mL). The layers were separated, the aqueous layer was back extractedwith CH₂Cl₂ (2×30 mL), and the combined organic layer was dried overNa₂SO₄. The solvent was evaporated and the crude product was purified onsilica gel column, eluting with 1-8% MeOH in CH₂Cl₂ to yield imidazole1086 as a thick oil which precipitated to white solid in diethyl ether(0.051 g, 22%). LCMS (ESI) m/e 409.0 (M+H)⁺.

Example 27 Synthesis of Compound 1101

Scheme 20 depicts the synthesis of compound 1101.

Synthesis of Alcohol 126

To a stirred solution of 0.050 g (0.14 mmol) of aldehyde 92 and 0.010 g(0.17 mmol) of aminoethanol in 5 ml of DMF was added 0.059 g (0.28 mmol)of NaB(OAc)₃H. The reaction mixture was stirred for 2 h. DMF was removedin vacuo, and the residue was purified by preparative TLC to give 0.055g of alcohol 126. MS (M+1): 438.

Synthesis of Alcohol 127

A solution of 0.050 g (0.11 mmol) of 126, 0.030 g (0.14 mmol) of(BOC)₂O, 0.038 g (0.46 mmol) of NaHCO₃ in 10 ml of THF:H₂O (4:1) wasstirred at 25° C. for 6 h. The reaction mixture was diluted with water(30 ml) and extracted with CH₂Cl₂ (50 ml×3). The combined organic layerswere washed with brine (40 ml), dried over MgSO₄, and concentrated togive 0.040 g of alcohol 127. MS (M+1): 501.

Synthesis of Compound 1101

A solution of 0.126 g (0.25 mmol) of alcohol 127 and 0.11 ml (0.75 mmol)of Et₃N in 5 ml of DMF was heated to 60° C. for 24 h. The reactionmixture was cooled and the solvent was removed in vacuo. The residue waspurified via preparative TLC to yield 0.033 g of compound 1101. MS(M+1): 428.

Example 28 Synthesis of Imidazole 1113

Scheme 21 depicts the synthesis of imidazole 1113.

A mixture of chloride 90 (113 mg, 0.3 mmol), 2-aminoimidazole sulfate127 (119 mg, 0.9 mmol), N,N-diisopropylethylamine (0.26 mL, 1.5 mmol)and KI (17 mg, 0.1 mmol) in DMF (5 mL) was stirred at room temperaturefor 12 h. The reaction was concentrated in vacuo, and the crude productwas purified by preparative thin layer chromatography (10:1:0.1 CH₂Cl₂:MeOH:NH₃.H₂O) to afford 90 mg of 1113 in a yield of 71%. MS (ESI): 424.0(100%, (M+H)⁺).

Example 29 Synthesis of Isoxazole 2001

Scheme 22 depicts the reaction leading to isoxazole 2001.Hydroxyisoxazole 201 was coupled to alcohol 51 using the Mitsunobureaction to yield isoxazole 2001.

Synthesis of isoxazole 2001

The known isoxazole 201 was synthesized from methyl tetrolate asreported in literature (Iwai, I. et al. Chem. Pharm. Bull. 1966, 14,1277-1286). To a suspension of isoxazole 201 (33 mg, 0.279 mmol),alcohol 51 (100 mg, 0.335 mmol) and triphenyl phosphine (95 mg, 0.363mmol) was added diisopropyl azodicarboxylate (DIAD, 0.072 mL, 0.363mmol) at −20° C. The reaction mixture was warmed to ambient temperatureand stirred for 3 h. The solution was concentrated and purified by flashchromatography (4% MeOH in 1:1 CH₂Cl₂/EtOAc) to yield 64 mg of 2001.LCMS (ESI) m/z 440 (M+H)⁺.

Example 30 Synthesis of Compounds 2002-2006

Scheme 23 illustrates the reductive amination chemistry leading tocompounds 2002-2006. Aldehyde 92 is treated with various amines in thepresence of a reducing agent to yield the desired targets.

Synthesis of Triazole 2002

A suspension of the aldehyde 92 (178 mg, 0.5 mmol) in THF (4.0 mL) wastreated with [1,2,4]triazol-4-ylamine (84 mg, 1.0 mmol) and acetic acid(0.02 mL) at room temperature, and the resulting reaction mixture wasstirred at room temperature for 1 h before lithium aluminumhydride (38mg, 1.0 mmol) was added at room temperature. The resulting reactionmixture was stirred at room temperature for an additional 1 h. When TLCand LCMS showed the reaction was complete, the reaction mixture wasconcentrated in vacuo, and the residue was directly purified by columnchromatography (0-5% MeOH/CH₂Cl₂ gradient elution) to afford the desiredtriazole 2002 (40 mg; 19%) as a yellow solid. LCMS (ESI) m/z 425 (M+H)⁺.

Synthesis of Isoxazole 2003

A suspension of aldehyde 92 (107 mg, 0.3 mmol) in MeOH (4.0 mL) and THF(1.0 mL) was treated with 3-methyl-isoxazol-5-ylamine (59 mg, 0.6 mmol)and sodium triacetoxyborohydride (127 mg, 0.6 mmol) at 25° C., and theresulting reaction mixture was stirred at 25° C. for 6 h. When TLC andLCMS showed the reductive amination reaction was complete, the reactionmixture was concentrated in vacuo. The residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford the desired isoxazole 2003 (12 mg; 9% yield) as a colorless oil,which solidified upon standing at room temperature in vacuo. LCMS (ESI)m/z 439 (M+H)⁺.

Synthesis of Isoxazole 2004

A solution of aldehyde 92 (107 mg, 0.3 mmol) in MeOH (3.0 mL) and THF(3.0 mL) was treated with 5-methyl-isoxazol-3-ylamine (59 mg, 0.6 mmol)and sodium triacetoxyborohydride (127 mg, 0.6 mmol) at 25° C., and theresulting reaction mixture was stirred at 25° C. for 6 h. When TLC andLCMS showed the reductive amination reaction was complete, the reactionmixture was concentrated in vacuo. The residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford isoxazole 2004 (41 mg; 31%) as a colorless oil, which solidifiedupon standing at room temperature in vacuo. LCMS (ESI) m/z 439 (M+H)⁺.

Synthesis of Carbamate 2005

A suspension of aldehyde 92 (142 mg, 0.4 mmol) in MeOH (4.0 mL) and THF(1.0 mL) was treated with 4-amino-piperidine-1-carboxylic acid ethylester (69 mg, 0.4 mmol) and sodium triacetoxyborohydride (160 mg, 0.8mmol) at 25° C., and the resulting reaction mixture was stirred at 25°C. for 6 h. When TLC and LCMS showed the reductive amination reactionwas complete, the reaction mixture was concentrated in vacuo. Theresidue was directly purified by flash column chromatography (0-5%MeOH—CH₂Cl₂ gradient elution) to afford carbamate 2005 (98 mg; 48%yield) as a colorless oil, which solidified upon standing at roomtemperature in vacuo. LCMS (ESI) m/z 513 (M+H)⁺.

Synthesis of Bicyclic Diamine 2006

A suspension of aldehyde 92 (142 mg, 0.4 mmol) in MeOH (4.0 mL) and THF(1.0 mL) was treated with 1-aza-bicyclo[2.2.2]oct-3-ylamine (80 mg, 0.4mmol) and sodium triacetoxyborohydride (160 mg, 0.8 mmol) at 25° C., andthe resulting reaction mixture was stirred at 25° C. for 6 h. When TLCand LCMS showed the reductive amination reaction was complete, thereaction mixture was concentrated in vacuo. The residue was directlypurified by flash column chromatography (0-5% MeOH—CH₂Cl₂ gradientelution) to afford diamine 2006 (71 mg; 38% yield) as a colorless oil,which solidified upon standing at room temperature in vacuo. LCMS (ESI)m/z 467 (M+H)⁺.

Example 31 Synthesis of Compounds 2007 and 2008 Synthesis of Amide 2007

To a solution of anthranilamide (74 mg, 0.532 mmol) and mesylate 52 (100mg, 0.229 mmol) in DMF (2.0 mL) was added Hunig's base (185 μL, 1.06mmol). The mixture was stirred at 80° C. for 16 h, then the mixture wasconcentrated by vacuum. The residue was directly isolated byreverse-phase preparative HPLC, to give 112 mg of 2007 as a white powderin 88% yield. LCMS (ESI) m/z 477 (M+H)⁺.

Synthesis of Amide 2008

To a solution of 3-aminothiophene-2-carboxamide (67 mg, 0.459 mmol) andmesylate 52 (100 mg, 0.229 mmol) in DMF (2.0 mL) was added Hunig's base(160 μL, 0.916 mmol). The mixture was stirred at 80° C. for 16 h, thenthe mixture was concentrated under vacuum. The residue was directlyisolated by flash chromatography on silica gel (5:100 MeOH/CH₂Cl₂ aseluant), to afford 51 mg of 2008 as a white powder in 46% yield. LCMS(ESI) m/z 482 (M+Na)⁺.

Example 32 Synthesis of Compounds 2009 and 2010

Scheme 24 depicts the synthesis of 2009 and 2010 from D- andL-cycloserine respectively via alkylation with mesylate 52.

Synthesis of Cycloserine Derivative 2009

A mixture of D-cycloserine 202 (0.22 g, 2.04 mmol) and mesylate 52 (0.30g, 0.68 mmol) in anhydrous CH₂Cl₂ (5 mL), MeOH (5 mL) and Hunig's base(2 mL) was heated to reflux for 3 h. The solvent was evaporated and thecrude was purified on silica gel column, eluting with CH₂Cl₂/MeOH 20:1then with CH₂Cl₂/MeOH/NH₄OH 20:1:0.04 to 16:1:0.04 to give a whitesolid. The isolated solid was titurated with Et₂O/CH₃CN 1:1 (15 mL) andthe suspension filtered to give analytically pure 2009 as a white solid(0.072 g, 24%). LCMS (ESI) m/z 443 (M+H)⁺.

Synthesis of Cycloserine Derivative 2010

Compound 2010 was synthesized from L-cycloserine 203 and mesylate 52 asdescribed above for the synthesis of 2009. LCMS (ESI) m/z 443 (M+H)⁺.

Example 33 Synthesis of Azetidine 2011

A mixture of aldehyde 92 (100 mg, 0.28 mmol) and tert-butyl3-amino-azetidine-1-carboxylate (58 mg, 0.34 mmol) in THF (2 mL) and DMF(0.5 mL) was stirred at room temperature for 1 h. Sodiumtriacetoxyborohydride (120 mg, 0.56 mmol) was added. After stirring atroom temperature for 2 h, the reaction was concentrated, and the residuewas dissolved in CH₂Cl₂, washed with water, and dried over MgSO₄. TheCH₂Cl₂ solution was treated with trifluoroacetic acid (0.5 mL) at roomtemperature. After stirring for 1 h, the mixture was concentrated andpurified by preparative thin layer chromatography (10:1:0.05CH₂Cl₂/MeOH/NH₃.H₂O) to afford 45 mg of 2011 in a yield of 39%. LCMS(ESI) m/z 413.1 (M+H)⁺.

Example 34 Synthesis of Thiadiazoles 2012-2013

As Scheme 25 illustrates, thiadiazole 2012 was synthesized fromchlorothiadiazole 205 by substitution with amine 54 followed by BOCdeprotection. Acylation of 2012 with aminoacid fragments affordedthiadiazoles 2013 and 2014.

Synthesis of chlorothiadiazole 205

To a solution of BOC-aminoacetoamidine 204 (3.11 g, 18 mmol) in CH₂Cl₂(60 mL) was added 3M NaOH (12.6 mL, 37.7 mmol) at −10° C. Under strongstirring, half of a solution of trichloromethanesulfenyl chloride(Cl₃CSCl, 1.96 mL, 18 mmol) in CH₂Cl₂ (30 mL) was slowly added. Then anadditional 3M NaOH (12.6 mL, 37.7 mmol) was added, followed by theremaining Cl₃CSCl solution. The mixture was stirred at −10° C. for 30min and then at 0° C. for 15 min before being diluted with ice-water (50mL) and extracted with in CH₂Cl₂ (2×80 mL). The combined organic layerwas washed with brine (1×20 mL), dried over Na₂SO₄ and the solvent wasevaporated. The crude residue was purified on silica gel eluting withhexanes/ethyl acetate 6:1, yielding 205 as a yellow oil (2.9 g; 65%).¹H-NMR (300 MHz, CDCl₃) δ 5.12 (s 1H), 4.42-4.40 (m, 2H), 1.29 (s, 9H).

Synthesis of Thiadiazole 2012

To a solution of the amine 54 (1.0 g, 2.8 mmol) in MeOH (15 mL) and DMF(3 mL) was added chlorothiadiazole 205 (800 mg, 3.1 mmol) and Hunig'sbase (1 mL, 5.6 mmol). The mixture was stirred at 50° C. overnight andthen poured into 5% Na₂CO₃/ice (20 mL) and extracted with 9:1CH₂Cl₂-isopropanol (2×100 mL). The combined organic layer was dried overNa₂SO₄ and the solvent evaporated. The crude residue was purified onsilica gel eluting with 10:1 ethyl acetate/CH₂Cl followed by 95:5 ethylacetate/MeOH, yielding white crystals, which were dissolved in 4M HCl indioxane (20 mL). The mixture was stirred at room temperature for 2 h.The suspension was filtered and washed with ether (2×10 mL), and driedat high vacuum, yielding 2012 (830 mg; 93%). LCMS (ESI) m/z 471 (M+H)⁺.

Synthesis of Thiadiazole 2013

To a solution of thiadiazole 2012 (150 mg, 0.30 mmol) in CH₂Cl₂ (4 mL)and DMF (3 mL) was added Hunig's base (0.16 mL, 0.90 mmol),(L)-BOC-Ala-OH (67 mg, 0.36 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 79mg, 0.42 mmol). The mixture was stirred overnight at room temperature,then additional amounts of (L)-BOC-Ala-OH (34 mg, 0.18 mmol), EDCI (40mg, 0.21 mmol) and Hunig's base (0.08 mL, 0.44 mmol) were added. Themixture was stirred at room temperature overnight, poured into 1NHCl-ice (20 mL), and extracted with CH₂Cl₂-isopropanol 95:5 (2×50 mL).The combined organic layer was washed with water (15 mL), 5% sodiumcarbonate (Na₂CO₃, 15 mL), water (15 mL), brine (15 mL), and then driedover Na₂SO₄ and the solvent evaporated. The crude residue was purifiedon silica gel eluting with ethyl acetate/MeOH 95:5. The residue wasdissolved in 4M HCl in dioxane (7 mL). The mixture was stirred at roomtemperature for 2 h and then evaporated. The residue was diluted withether (3 mL), filtered, and the solid washed with ether (2×5 mL), thendried at high vacuum, yielding 2013 (122 mg; 91%). LCMS (ESI) m/z 542(M+H)⁺.

Synthesis of Thiadiazole 2014

To a solution of thiadiazole 2012 (150 mg, 0.30 mmol) in CH₂Cl₂ (3 mL)and DMF (3 mL) was added Hunig's base (0.08 mL, 0.45 mmol) and(L)-BOC-Lys (BOC)—OSu (157 mg, 0.36 mmol). The mixture was stirredovernight at room temperature, poured into 5% Na₂CO₃-ice (20 mL),extracted with CH₂Cl₂-isopropanol 95:5 (3×50 mL), dried over Na₂SO₄ andthe solvent evaporated. The crude residue was purified on silica geleluting with ethyl acetate followed by 5:1 ethyl acetate/MeOH. TheBOC-protected material obtained was dissolved in 4M HCl in dioxane (6mL) and MeOH (2 mL), stirred at room temperature for 3 h and thenevaporated. The residue was diluted with ether (6 mL), filtered, washedwith ether (2×5 mL) and dried at high vacuum, yielding 2014 (100 mg;50%). LCMS (ESI) m/z 599 (M+H)⁺.

Example 35 Synthesis of Compounds 2015-2019

As Scheme 26 illustrates, benzyl chloride 90 served as alkylating agentfor thiolates or thiols to afford compounds 2015-2019.

Synthesis of Tetrazole 2015

A solution of chloride 90 (0.15 g, 0.40 mmol) in DMF (2 mL) was treatedwith 5-mercapto-4-methyltetrazole, sodium salt, dihydrate (0.14 g, 0.80mmol) and stirred at 23° C. for 0.5 h. The reaction mixture was dilutedwith water and the precipitate was recovered by vacuum filtration toafford tetrazole 2015 as a white powder (63%). LCMS (ESI) m/z 456(M+H)⁺.

Synthesis of Triazole 2016

Tetrazole 2016 was prepared with chloride 90 (0.30 g, 0.80 mmol) and4-mercapto-1,2,3-triazole, sodium salt, (0.20 g, 1.6 mmol) according tothe procedure above used to synthesize tetrazole 2015 to afford 2016 asa yellow powder (0.29 g, 0.66 mmol, 82%). LCMS (ESI) m/z 442 (M+Na)⁺.

Synthesis of Compound 2017

Compound 2017 was prepared with chloride 90 (0.20 g, 0.53 mmol) and2-thiobarbituric acid, sodium salt, (0.18 g, 1.1 mmol) according to theprocedure above used to synthesize tetrazole 2015 to afford 2017 as awhite powder (0.078 g, 0.16 mmol; 30%). LCMS (ESI) m/z 507 (M+Na)⁺.

Synthesis of Mercaptopyridine 2018

A solution of chloride 90 (0.20 g, 0.53 mmol) in DMF (2.7 mL) wastreated with cesium carbonate (0.21 g, 0.64 mmol) and 2-mercaptopyridine(0.071 g, 0.64 mmol) and was stirred at 23° C. for 0.5 h. The reactionmixture was diluted with water and the precipitate was recovered byvacuum filtration to afford 2018 as a yellow powder (91%). LCMS (ESI)m/z 452 (M+H)⁺.

Synthesis of Mercaptopyridine 2019

Mercaptopyridine 2019 was prepared with chloride 90 (0.20 g, 0.53 mmol),cesium carbonate (0.21 g, 0.64 mmol), and 4-mercaptopyridine (0.071 g,0.64 mmol) according to the procedure above used to synthesize 2018 toafford a yellow powder (0.078 g, 0.16 mmol; 30%). LCMS (ESI) m/z 452(M+H)⁺.

Example 36 Synthesis of Sulfoxides 2020-2023

As Scheme 27 illustrates, sulfides 2015, 2016, 2019, and 2018 wereoxidized under controlled conditions to afford sulfoxides 2020-2023respectively.

Synthesis of Sulfoxide 2020

A solution of 2015 (0.020 g, 0.044 mmol) in chloroform (0.44 mL) andmethanol (0.050 mL) was treated with 3-chloroperoxybenzoic acid (77%,0.010 g, 0.044 mmol) and stirred at 23° C. for 12 h. The reactionmixture was diluted with methylene chloride, washed with saturatedaqueous sodium bicarbonate, dried over Na₂SO₄, and the solvent removedin vacuo. The crude product was purified with preparative TLC (1:4.5:4.5MeOH/ethyl acetate/CH₂Cl₂) to afford 2020 as a white powder (3.6 mg,0.008 mmol; 19%). LCMS (ESI) m/z 495 (M+Na)⁺.

Synthesis of Sulfoxide 2021

Sulfoxide 2021 was prepared from sulfide 2016 (0.030 g, 0.068 mmol) and3-chloroperoxybenzoic acid (77%, 0.015 g, 0.068 mmol) according to theprocedure described above for the synthesis of sulfoxide 2020 to afforda white powder (0.021 g, 0.046 mmol; 68%). LCMS (ESI) m/z 480 (M+Na)⁺.

Synthesis of sulfoxide 2022

Sulfoxide 2022 was prepared from sulfide 2019 (0.080 g, 0.18 mmol) and3-chloroperoxybenzoic acid (77%, 0.040 g, 0.18 mmol) according to theprocedure described above for the synthesis of sulfoxide 2020 to afforda white powder (0.021 g, 0.094 mmol; 52%). LCMS (ESI) m/z 468 (M+H)⁺.

Synthesis of Sulfoxide 2023

Sulfoxide 2023 was prepared from sulfide 2018 (0.10 g, 0.22 mmol) and3-chloroperoxybenzoic acid (77%, 0.050 g, 0.22 mmol) according to theprocedure described above for the synthesis of sulfoxide 2020 to afforda white powder (0.068 g, 0.15 mmol; 66%). LCMS (ESI) m/z 466.

Example 37 Synthesis of Sulfones 2024 and 2025

As Scheme 28 illustrates, sulfides 2015 and 2016 were oxidized withexcess 3-chloroperoxybenzoic acid to afford sulfones 2024 and 2025.

Synthesis of Sulfone 2024

A solution of sulfide 2015 (0.020 g, 0.044 mmol) in chloroform (0.44 mL)and methanol (0.050 mL) was treated with 3-chloroperoxybenzoic acid(77%, 0.030 g, 0.13 mmol) and stirred at 23° C. for 1 h and then heatedto 50° C. for 12 h. The reaction mixture was cooled to 23° C., dilutedwith methylene chloride, washed with saturated aqueous sodiumbicarbonate, dried (Na₂SO₄), and the solvent removed in vacuo. The crudeproduct was purified by preparative TLC (5% MeOH in CH₂Cl₂) to affordsulfone 2024 as a white powder (3.6 mg; 17%). LCMS (ESI) m/z 489 (M+H)⁺.

Synthesis of Sulfone 2025

A solution of sulfide 2016 (0.050 g, 0.11 mmol) in chloroform (1.1 mL)and methanol (0.1 mL) was treated with 3-chloroperoxybenzoic acid (77%,0.076 g, 0.34 mmol) and stirred at 23° C. for 2 h. The precipitate wasrecovered through vacuum filtration to yield sulfone 2025 as a whitesolid (0.020 g; 37%). LCMS (ESI) m/z 474 (M+H)⁺.

Example 38 Synthesis of Mercaptotriazole 2026

A solution of mesylate 64 (0.012 g, 0.027 mmol) in DMF (0.14 mL) wastreated with 4-mercapto-1,2,3-triazole, sodium salt (7 mg, 0.054 mmol)and was stirred at 45° C. for 2 h. The solvent was removed in vacuo andthe crude product was purified by preparative TLC (5% MeOH in CH₂Cl₂) toafford mercaptotriazole 2026 as a white solid (3.1 mg; 24%). LCMS (ESI)m/z 456 (M+H)⁺.

Example 39 Synthesis of Compounds 2027-2033

As Scheme 29 illustrates, benzyl chloride 90 was used to alkylate thiols207a-g to provide compounds 2027-2033 respectively.

Synthesis of Tetrazole 2027

Benzyl chloride 90 (0.20 g, 0.53 mmol) was dissolved in DMF (5 mL).Thiol 207a (62 mg, 0.53 mmol) and cesium carbonate (0.20 g, 0.64 mmol)were added sequentially and the resulting slurry stirred at roomtemperature for 4 h. The mixture was poured into 70 mL H₂O and stirredfor 1 h. The solids were filtered, rinsed with ether and dried undervacuum to afford tetrazole 2027 as a brown solid (187 mg, 0.36 mmol).LCMS (ESI) m/z 514 (M+H)⁺.

Synthesis of Triazole 2028

Triazole 2028 was synthesized by the process described for 2027 aboveusing thiol 207b in place of 207a to yield 138 mg of triazole 2028 as ayellow solid (0.30 mmol). LCMS (ESI) m/z 457 (M+H)⁺.

Synthesis of Thiadiazole 2029

Thiadiazole 2029 was synthesized by the process described for 2027 aboveusing thiol 207c in place of 207a to yield 147 mg of thiadiazole 2029 asa white solid (0.32 mmol). LCMS (ESI) m/z 481 (M+Na)⁺, 522(M+Na+CH₃CN)⁺.

Synthesis of Thiazole 2030

Thiazole 2030 was synthesized by the process described for 2027 aboveusing thiol 207d in place of 207a to yield 129 mg of thiazole 2030 as awhite solid (0.28 mmol). LCMS (ESI) m/z 458 (M+H)⁺, 521 (M+Na+CH₃CN).

Synthesis of Thiazole 2031

Thiazole 2031 was synthesized by the process described for 2027 aboveusing thiol 207e in place of 207a to yield 155 mg of thiazole 2031 as anoff-white solid (0.33 mmol). LCMS (ESI) m/z 472 (M+H)⁺.

Synthesis of Imidazole 2032

Imidazole 2032 was synthesized by the process described for 2027 aboveusing thiol 207f in place of 207a to yield 91 mg of imidazole 2032 as awhite solid (0.21 mmol). LCMS (ESI) m/z 441 (M+H)⁺.

Synthesis of Triazole 2033

Triazole 2033 was synthesized by the process described for 2027 aboveusing thiol 207 g in place of 207a to yield 91 mg of triazole 2033 as awhite solid (0.21 mmol). LCMS (ESI) m/z 456 (M+H)⁺, 478 (M+Na)⁺, 519(M+Na+CH₃CN)⁺.

Example 40 Synthesis of Compounds 2034-2039

As Scheme 30 illustrates, compounds 2027 and 2029-2033 were oxidized toafford sulfoxides 2034-2039 respectively.

Synthesis of Sulfoxide 2034

Tetrazole 2027 (80 mg, 0.16 mmol) was dissolved in 3:1 CH₁Cl₂/MeOH (3mL). m-CPBA was added (75% pure; 39 mg, 0.17 mmol) and the mixture wasstirred at room temperature for 6 h. The reaction mixture was pouredinto 50 mL ether and stirred for 1 h. The solids were filtered and driedin vacuo to give sulfoxide 2034 as an off-white solid (55 mg, 0.10mmol). LCMS (ESI) m/z 530 (M+H)⁺.

Synthesis of Sulfoxide 2035

Sulfoxide 2035 was synthesized by the process described above for 2034starting with thiadiazole 2029 in place of tetrazole 2027 to yield 39 mgof 2035 as a white solid (0.08 mmol). LCMS (ESI) m/z 497 (M+Na)^(, 538)(M+Na+CH₃CN)⁺.

Synthesis of Sulfoxide 2036

Sulfoxide 2036 was synthesized by the process described above for 2034starting with thiazole 2030 in place of tetrazole 2027 to yield 48 mg of2036 as an off-white solid (0.10 mmol). LCMS (ESI) m/z 496 (M+Na)⁺, 537(M+Na+CH₃CN)⁺.

Synthesis of Sulfoxide 2037

Sulfoxide 2037 was synthesized by the process described above for 2034starting with thiazole 2031 in place of tetrazole 2027 to yield 44 mg of2037 as an off-white solid (0.09 mmol). LCMS (ESI) m/z 488 (M+H)⁺, 510(M+Na)⁺, 551 (M+Na+CH₃CN)⁺.

Synthesis of Sulfoxide 2038

Sulfoxide 2038 was synthesized by the process described above for 2034starting with imidazole 2032 in place of tetrazole 2027 to yield 51 mgof 2038 as a white solid (0.11 mmol). LCMS (ESI) m/z 457 (M+H)⁺.

Synthesis of Sulfoxide 2039

Sulfoxide 2039 was synthesized by the process described above for 2034starting with triazole 2033 in place of tetrazole 2027 to yield 48 mg of2039 as a white solid (0.10 mmol). LCMS (ESI) m/z 472 (M+H)⁺⁴⁹⁴ (M+Na)⁺,535 (M+Na+CH₃CN)⁺.

Example 41 Synthesis of Compound 2040

A solution of mesylate 106 (43.7 mg, 1.0 mmol) in anhydrous DMF (4.0 mL)was treated with 1H-5-mercapto-1,2,3-triazole sodium salt (24.6 mg, 2.0mmol) at room temperature, and the resulting reaction mixture wasstirred at room temperature overnight. When TLC and LCMS showed that thereaction was complete, the reaction mixture was concentrated in vacuo,and the residue was directly purified by flash column chromatography(0-5% MeOH—CH₂Cl₂ gradient elution) to afford mercaptotriazole 2040(29.0 mg; 66%) as a pale-yellow solid. LCMS (ESI) m/z 443 (M+H)⁺.

Example 42 Synthesis of Compounds 2043 and 2044 Synthesis of Compound2043

A solution of amine 54 (0.070 g, 0.20 mmol) in DMF (1.0 mL) was treatedwith triethylamine (0.055 mL, 0.40 mmol) and1-methyl-1H-imidazole-4-sulfonyl chloride (0.039 mg, 0.22 mmol) andstirred at 23° C. for 30 minutes. The solvent was removed in vacuo, andthe crude product was purified by flash chromatography (4.5:4.5:1methylene chloride/ethyl acetate/methanol) to afford compound 2043(0.054 g, 0.11 mmol, 55%). MS (ESI): 502 (M+H)⁺.

Synthesis of Compound 2044

A solution of amine 54 (0.070 g, 0.20 mmol) in DMF (1.0 mL) was treatedwith triethylamine (0.055 mL, 0.40 mmol) and6-morpholin-4-yl-pyridine-3-sulfonyl chloride (0.057 g, 0.22 mmol) andstirred at 23° C. for 30 minutes. The solvent was removed in vacuo, andthe crude product was purified by flash chromatography (0-10% methanolin 1:1 ethyl acetate/methylene chloride) to afford compound 2044 (0.052g, 0.09 mmol, 45%). MS (ESI): 584 (M+H)⁺.

Example 43 Synthesis of Compound 2047

A solution of chloride 90 (0.19 g, 0.50 mmol) in DMF (5 mL) was treatedwith 3-mercapto-1,2,4-triazole (0.20 g, 1.0 mmol) and Cs₂CO₃ (0.33 g,1.0 mmol), and stirred at 23° C. for 1 h. The reaction mixture wasdiluted with H₂O (45 mL), and the resulting precipitate filtered, washedwith H₂O and dried under vacuum to afford compound 2047 (0.139 g, 0.315mmol, 63%) as a white powder. MS (ESI): 442 (M+H)⁺.

Example 44 Synthesis of Compound 2050

Scheme 31 depicts the synthesis of compound 2050.

To a solution of 0.050 g (0.15 mmol) of aldehyde 92 and 0.026 g (0.30mmol) of aminoisoxazole in 2 ml of TFA at 25° C. was added 0.018 g (0.30mmol) of sodium cyanoborohydride (NaBH₃CN). The reaction mixture wasstirred at 25° C. for 4 h. The TFA was removed, and the residue waspurified by preparative TLC to give 0.040 g of compound 2050. MS (M+1):425.

Example 45 Synthesis of Compounds 3001-3004

As Scheme 32 illustrates, bromide 301 was coupled to boronate 81 toyield pyridyl derivative 3001. Successive oxidations provided sulfoxide3002, sulfone 3003, and the pyridyl N-oxide 3004.

Synthesis of Bromide 301

A suspension of 4-bromomethylpyridine hydrochloride (1.59 g, 6.3 mmol)in THF (10 mL) was treated dropwise with a solution of potassiumcarbonate (3.33 g, 24.0 mmol) in H₂O (6 mL) at 0-5° C., and theresulting mixture was stirred at 0-5° C. for 10 min before being treateddropwise with a solution of 4-bromo-benzenethiol (1.14 g, 6.0 mmol) inTHF (5.0 mL) at 0-5° C. under N₂. The resulting reaction mixture wassubsequently stirred at 0-5° C. for an additional 20 min. When TLC andLCMS showed that the reaction was complete, the reaction mixture wastreated with water (15 mL) and ethyl acetate (25 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(2×20 mL). The combined organic extracts were washed with water (2×15mL) and saturated aqueous NaCl solution (10 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography (5-25% EtOAc-hexane gradient elution) to afford thedesired 4-(4-bromo-phenylsulfanylmethyl)pyridine 301 (1.374 g; 82%) as apale-yellow solid, which was directly used in subsequent reactions.

Synthesis of Compound 3001

A solution of boronate 81 (200 mg, 0.53 mmol) and bromide 301 (150 mg,0.53 mmol) in toluene (9 mL) was treated with solid potassium carbonate(220 mg, 1.6 mmol), ethanol (3.0 mL) and H₂O (3.0 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(16 mg, 0.013 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed up to reflux for 2 h. When LCMS showed that the reaction wascomplete, the reaction mixture was cooled down to room temperaturebefore being treated with water (10 mL) and ethyl acetate (20 mL). Thetwo layers were separated, and the aqueous layer was extracted withethyl acetate (2×10 mL). The combined organic extracts were washed withwater (2×10 mL) and saturated aqueous NaCl solution (10 mL), dried overMgSO₄, and concentrated in vacuo. The residue was then purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordcompound 3001 (177 mg; 74%) as a yellow oil, which solidified uponstanding at room temperature in vacuo. LCMS (ESI) m/z 452 (M+H)⁺.

Synthesis of Sulfoxide 3002

A solution of compound 3001 (58 mg, 0.13 mmol) in CH₂Cl₂ (2.0 mL) andMeOH (0.5 mL) was treated with m-CPBA (22 mg, 0.13 mmol) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 2 h. The solvents were removed, and the residue wasdirectly purified by flash column chromatography (0-5% MeOH—CH₂Cl₂gradient elution) to afford sulfoxide 3002 (43 mg; 71%) as a colorlessoil, which solidified upon standing at room temperature in vacuo. LCMS(ESI) m/z 468 (M+H)⁺.

Synthesis of Sulfone 3003

A solution of sulfoxide 2002 (22 mg, 0.047 mmol) in CH₂Cl₂ (2.0 mL) andMeOH (0.5 mL) was treated with nm-CPBA (9.0 mg, 0.047 mmol) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 2 h. The solvents were removed, and the residue wasdirectly purified by flash column chromatography (0-5% MeOH—CH₂Cl₂gradient elution) to afford sulfone 3003 (16 mg; 71%) as a colorlessoil, which solidified upon standing at room temperature in vacuo. LCMS(ESI) m/z 484 (M+H)⁺.

Synthesis Of Pyridyl N-Oxide 3004

A solution of sulfone 3003 (16 mg, 0.033 mmol) in CH₂Cl₂ (1.0 mL) andMeOH (0.5 mL) was treated with m-CPBA (6.0 mg, 0.033 mmol) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 2 h. The solvents were removed, and the residue wasdirectly purified by flash column chromatography (0-5% MeOH—CH₂Cl₂gradient elution) to afford the pyridyl N-oxide 3004 (11 mg; 67% yield)as colorless oil, which solidified upon standing at room temperature invacuo. LCMS (ESI) m/z 500 (M+H)⁺.

Example 46 Synthesis of Compound 3005

Scheme 33 illustrates the synthesis of compound 3005.

Synthesis of Bromide 303

4-bromobenzenesulfonyl chloride 302 (2.56 g, 10 mmol) was added to asolution of 4-aminomethylpyridine (1.08 g, 10 mmol) and triethylamine (2mL, 14.3 mmol) in THF (20 mL) at 0° C. After stirring at sametemperature for 1 h, 50 mL of cool water was added. A white solid wascollected by filtration, washing with EtOAc and dried in vacuum to give3.10 g of bromide 303 in a yield of 95%.

Synthesis of Compound 3005

Bromide 303 (327 mg, 1 mmol), boronate 81 (378 mg, 1 mmol), Pd(dppf)₂Cl₂(40 mg, 0.05 mmol) and K₂CO₃ (414 mg, 3 mmol) were dissolved 8 mL of amixture of dioxane:EtOH: H₂O (3:1:1) under argon atmosphere. Afterheating at 100° C. for 12 hours, the reaction was added to 20 mL of coolwater. The organic solvent was removed in vacuo and the crude productwas collected by filtration. The crude product was treated with activecharcoal and recrystallized in a mixed solvent system (1:2:2MeOH:CH₂Cl₂:acetone) to give 155 mg of 3005 in a yield of 31%. MS (ESI):499.1 (100%, (M+H)⁺).

Example 47 Synthesis of Amide 4008

A solution of amine 54 (36 mg, 0.1 mmol) in DMF was treated withquinoline-4-carboxylic acid (26 mg, 0.15 mmol, 1.5 equiv) at 25° C.under N₂, and the resulting mixture was treated with EDCI (28.5 mg, 0.15mmol, 1.5 equiv) at 25° C. under N₂. The reaction mixture wassubsequently stirred at 25° C. for 12 h. When TLC and HPLC showed thecoupling reaction was complete, the reaction mixture was concentrated invacuo. The residue was then directly purified by flash columnchromatography (0-7% MeOH—CH₂Cl₂ gradient elution) to afford the desiredamide 4008 (36.4 mg, 71% yield) as an off-white powder. LCMS (ESI) m/e513 (M⁺+H).

Example 48 General Synthesis of Carboxylic Acid-Loaded Tfp Resins andSynthesis of Amide 4011

A suspension of polymeric 4-hydroxy-2,3,5,6-tetrafluorophenol (TFP, J.Comb. Chem. 2000, 2, 691) amide resin (1.00 g, 1.27 mmol) in DMF (10 mL)was shaken for 10 minutes in a 70 mL polypropylene cartridge and thentreated with indole-6-carboxylic acid (1.02 g, 6.35 mmol),3-hydroxybenzotriazole (18 mg, 0.13 mmol), and diisopropylcarbodiimide(1.2 mL, 7.6 mmol). The reaction mixture was shaken for 18 h at 23° C.,and then the resin was washed with DMF (10×50 mL), THF (10×50 mL), andmethylene chloride (10×50 mL) and dried in vacuo.

A suspension of the above TFP ester (35 mg) in 1 mL of DMF was treatedwith amine 54 (10 mg, 0.027 mmol) and shaken for 18 h in a 10 mLpolypropylene cartridge. The filtrate was collected and dried to giveamide 4011 (11 mg, 0.022 mmol, 81%) as a yellow solid. ¹HNMR (300 MHz,10:1 CDCl₃: CD₃OD): δ 7.89 (s, 1H), 7.75-7.71 (m, 1H), 7.55-7.52 (m,1H), 7.46-7.30 (m, 6H), 7.16 (dd, J=8, 2 Hz, 1H), 6.45-6.44 (m, 1H),4.70-4.68 (m, 1H), 4.60-4.59 (m, 2H), 4.03-3.97 (m, 1H), 3.73-3.71 (m,4H), 3.58-3.42 (m, 2H), 3.27-3.25 (m, 1H), 1.90 (s, 3H). LCMS (ESI) m/e501.0 (M+H)⁺.

Example 49 Synthesis of Amides 4010 and 4012-4105 Synthesis of Amide4010

Amide 4010 was prepared from the TFP ester ofN-methylpyrrole-2-carboxylic acid (477 mg, 3.81 mmol), which wasprepared according to the general method of Example 48. The TFP esterwas reacted with amine 54 using the acylation procedure of Example 48 tosynthesize amide 4011. The desired amide 4010 was obtained as a solid(10 mg, 0.022 mmol, 81%). ¹HNMR (300 MHz, 10:1 CDCl₃: CD₃OD): δ7.71-7.56 (m, 6H), 7.33 (dd, J=9, 2 Hz, 1H), 6.93-6.92 (m, 1H), 6.77(dd, J=4, 2 Hz, 1H), 6.55 (dd, J=12, 6 Hz, 2H), 6.27 (dd, J=4, 3 Hz,1H), 4.77-4.69 (m, 1H), 4.54-4.52 (m, 2H), 4.02-3.96 (m, 1H), 3.90 (s,3H), 3.73 (dd, J=9, 7 Hz, 1H), 3.62-3.58 (m, 2H), 1.96 (s, 3H). LCMS(ESI) m/e 465.0 (M+H)⁺.

Synthesis of Amide 4012

Amide 4012 was prepared from the TFP ester of 3-methylsulfonylbenzoicacid (1.27 g, 6.35 mmol), which was prepared according to the generalmethod of Example 48. The TFP ester was reacted with amine 54 using theacylation procedure of Example 48 to synthesize amide 4011. The desiredamide 4012 was obtained as a solid (13 mg, 0.024 mmol, 89%). ¹HNMR (300MHz, 10:1 CDCl₃: CD₃OD): δ 8.31-8.30 (m, 1H), 8.14-8.11 (m, 1H),8.00-7.97 (m, 1H), 7.64-7.58 (m, 2H), 7.45-7.29 (m, 6H), 7.12 (dd, J=9,2 Hz, 1H), 4.73-4.71 (m, 1H), 4.59-4.58 (m, 2H), 4.05-3.99 (m, 1H), 3.73(dd, J=9, 7 Hz, 1H), 3.61-3.44 (m, 6H), 3.30-3.27 (m, 1H), 3.03 (s, 3H).LCMS (ESI) m/e 540.1 (M+H)⁺.

Synthesis of Amide 4013

Amide 4013 was prepared from the TFP ester of 4-fluorobenzoic acid (890mg, 6.35 mmol), which was prepared according to the general method ofExample 48. The TFP ester was reacted with amine 54 using the acylationprocedure of Example 48 to synthesize amide 4011. The desired amide 4013was obtained as a solid (12 mg, 0.025 mmol, 93%). LCMS (ESI) m/e 480.0(M+H)⁺.

Synthesis of Amide 4014

Amide 4014 was prepared from the TFP ester of piperonylic acid (1.05 g,6.35 mmol), which was prepared according to the general method ofExample 48. The TFP ester was reacted with amine 54 using the acylationprocedure of Example 48 to synthesize amide 4011. The desired amide 4014was obtained as a solid (13 mg, 0.026 mmol, 96%). ¹HNMR (300 MHz,CDCl₃): δ 7.72-7.70 (m, 1H), 7.54-7.28 (m, 8H), 7.24-7.23 (m, 1H), 7.17(dd, J=9, 2 Hz, 1H), 5.93 (s, 2H), 4.65-4.79 (m, 1H), 4.54-4.52 (m, 2H),4.05-3.99 (m, 1H), 3.72 (dd, J=9, 7 Hz, 1H), 3.55-3.48 (m, 2H),3.28-3.26 (m, 2H), 1.92 (s, 3H). LCMS (ESI) nm/e 506.0 (M+H)⁺.

Synthesis of Amide 4015

Amide 4015 was prepared from the TFP ester of5-methoxyindole-2-carboxylic acid (486 mg, 2.54 mmol), which wasprepared according to the general method of Example 48. The TFP esterwas reacted with amine 54 using the acylation procedure of Example 48 tosynthesize amide 4011. The desired amide 4015 was obtained as a solid(10 mg, 0.019 mmol, 70%). ¹HNMR (300 MHz, 10:1 CDCl₃: CD₃OD): δ7.87-7.79 (m, 1H), 7.48-7.14 (m, 7H), 6.94 (s, 1H), 6.89-6.81 (m, 2H),4.67-4.61 (m, 1H), 4.54-4.52 (m, 2H), 4.02-3.93 (m, 2H), 3.71-3.61 (s,3H), 1.89 (s, 3H). LCMS (ESI) m/e 531.1 (M+H)⁺.

Example 50 Synthesis of Amine 4016

A solution of amine 54 (36 mg, 0.1 mmol) in a mixture of THF and DMF(3:1, v/v) was treated with quinoline-4-carboxaldehyde (16 mg, 0.1 mmol,1.0 equiv) at 25° C. under argon, and the resulting reaction mixture wasstirred at 25° C. for 30 min before being treated with sodiumtriacetoxyborohydride (NaB(OAc)₃H, 33 mg, 0.15 mmol, 1.5 equiv) at 25°C. The reaction mixture was subsequently stirred at 25° C. for 6 h. WhenTLC and HPLC showed the reductive amination reaction was complete, thereaction mixture was concentrated in vacuo. The residue was thendirectly purified by flash column chromatography (0-7% MeOH—CH₂Cl₂gradient elution) to produce the desiredN-[3-(2-fluoro-4′-{[(quinolin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide4016 (32.9 mg, 66% yield) as pale-yellow oil, which solidified uponstanding at room temperature in vacuo. ¹H NMR (300 MHz, DMSO-d₆) δ 1.85(s, 3H, COCH₃), 3.44 (t, 2H, J=5.4 Hz), 3.79 (dd, 1H, J=6.4, 9.2 Hz),3.88 (s, 2H), 4.17 (t, 1H, J=9.1 Hz), 4.30 (s, 2H), 4.77 (m, 1H), 7.41(dd, 1H, J=2.0, 8.0 Hz), 7.51-7.63 (m, 8H, aromatic-H), 7.74 (t, 1H,J=8.0 Hz), 8.04 (d, 1H, J=8.0 Hz), 8.18 (d, 1H, J=8.0 Hz), 8.27 (t, 1H,J=5.8 Hz, NHCOCH₃), 8.87 (d, 1H, J=8.0 Hz). LCMS (ESI) nm/e 499 (M+H)⁺.

Example 51 Synthesis of Amines 4018-4026 Synthesis of Amine 4018

To a solution of 0.032 g (0.089 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.009 g (0.080 mmol) of4-pyridylcarboxaldehyde and 0.027 g (0.12 mmol) of sodiumtriacetoxyborohydride at room temperature. The reaction mixture wasallowed to stir at 25° C. until the aldehyde was consumed based on TLCanalysis. The solvents of the reaction were removed via rotaryevaporation and the residue was then purified on a preparative TLC plateto give 7.0 mg of 4018. ¹H NMR (300 MHz, CD₃OD): δ 8.57 (s, 1H), 8.48(d, J=4.2 Hz, 1H), 7.91-7.33 (a series of multiplet peaks, 9H), 2.05 (s,3H). LCMS (ESI) nm/e 449 (M+H)⁺.

Synthesis of Amine 4019

To a solution of 0.080 g (0.22 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.032 g (0.20 mmol) of2-quinolinecarboxaldehyde and 0.094 g (0.44 mmol) of sodiumtriacetoxyborohydride at room temperature. The reaction mixture wasallowed to stir at 25° C. until the aldehyde was consumed based on TLCanalysis. The solvents of the reaction were removed via rotaryevaporation, and the residue was then purified on a preparative TLCplate to give 44 mg of 4019. ¹H NMR (300 MHz, CD₃OD+CDCl₃): δ 8.32 (d,J=5.4 Hz, 1H), 8.06 (d, J=5.4 Hz, 1H), 7.94 (d, J=6 Hz, 1H), 7.79-7.36(a series of multiplet peaks, 10H), 4.83 (m, 1H), 3.97 (s, 1H), 2.05 (s,3H). LCMS (ESI) m/e 499 (M+H)⁺.

Synthesis of 4020

To a solution of 0.080 g (0.22 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) was added 0.030 g (0.20 mmol) of2-benzofurancarboxaldehyde and 0.094 g (0.44 mmol) of sodiumtriacetoxyborohydride at room temperature. The reaction mixture wasallowed to stir at 25° C. until the aldehyde was consumed based on TLCanalysis. The solvents of the reaction were removed via rotaryevaporation, and the residue was then purified on a preparative TLCplate to give 49 mg of 4020. ¹H NMR (300 MHz, CD₃OD+CDCl₃): δ 7.44-7.01(a series of multiplet peaks, 11H), 6.62 (s, 1H), 3.92 (s, 2H), 3.82 (s,2H), 3.75-3.60 (m, 1H). LCMS (ESI) nm/e 488 (M+H)⁺.

Synthesis of Amine 4021

To a solution of 0.080 g (0.22 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.032 g (0.20 mmol) of3-quinolinecarboxaldehyde and 0.094 g (0.44 mmol) of sodiumtriacetoxyborohydride at room temperature. The reaction mixture wasallowed to stir at 25° C. until the aldehyde was consumed based on TLCanalysis. The solvents of the reaction was removed via rotaryevaporation, and the residue was then purified on a preparative TLCplate to give 49 mg of 4021. ¹H NMR (300 MHz, CD₃OD+CDCl₃): δ 8.89 (s,1H), 8.33 (s, 1H), 8.03 (d, J=5.4 Hz, 1H), 7.95 (d, J=5.4 Hz, 1H),7.80˜7.34 (a series of multiple peaks, 9H), 1.98 (s, 3H). LCMS (ESI) m/e499 (M+H)⁺.

Synthesis of Amine 4022

To a solution of 0.100 g (0.28 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.042 g (0.27 mmol) of1-naphthaldehyde and 0.119 g (0.56 mmol) of sodium triacetoxyborohydrideat room temperature. The reaction mixture was allowed to stir at 25° C.until the aldehyde was consumed based on TLC analysis. The solvents ofthe reaction were removed via rotary evaporation, and the residue wasthen purified on a preparative TLC plate to give 49 mg of 4022. ¹H NMR(300 MHz, CD₃OD+CDCl₃): δ 7.98˜7.24 (a series of multiple peaks, 14H),2.00 (s, 3H). LCMS (ESI) nm/e 498 (M+H)⁺.

Synthesis of Amine 4023

To a solution of 0.100 g (0.28 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.024 g (0.25 mmol) of3-furaldehyde and 0.119 g (0.56 mmol) of sodium triacetoxyborohydride atroom temperature. The reaction mixture was allowed to stir at 25° C.until the aldehyde was consumed based on TLC analysis. The solvents ofthe reaction were removed via rotary evaporation, and the residue wasthen purified on a preparative TLC plate to give 32 mg of 4023. ¹H NMR(300 MHz, CD₃OD+CDCl₃): δ 7.50-7.22 (a series of multiple peaks, 9H),6.39 (s, 1H), 1.90 (s, 3H). LCMS (ESI) nm/e 438 (M+H)⁺.

Synthesis of Amine 4024

To a solution of 0.100 g (0.28 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.027 g (0.25 mmol) of2-pyridylcarboxaldehyde and 0.089 g (0.42 mmol) of sodiumtriacetoxyborohydride at room temperature. The reaction mixture wasallowed to stir at 25° C. until the aldehyde was consumed based on TLCanalysis. The solvents of the reaction was removed via rotaryevaporation, and the residue was then purified on a preparative TLCplate to give 30.0 mg of 4024. ¹H NMR (300 MHz, CD₃OD): δ 8.39 (s, 1H),8.30 (d, J=2.1 Hz, 1H), 7.70˜7.21 (a series of multiplet peaks, 9H),1.86 (s, 3H). LCMS (ESI) m/e 449 (M+H)⁺.

Synthesis of Amine 4025

To a solution of 0.100 g (0.28 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.027 g (0.25 mmol) of3-pyridylcarboxaldehyde and 0.089 g (0.42 mmol) of sodiumtriacetoxyborohydride at room temperature. The reaction mixture wasallowed to stir at 25° C. until the aldehyde was consumed based on TLCanalysis. The solvents of the reaction were removed via rotaryevaporation, and the residue was then purified on a preparative TLCplate to give 30.0 mg of 4025. ¹H NMR (300 MHz, CD₃OD): δ 8.57 (s, 1H),8.48 (d, J=4.2 Hz, 1H), 7.91-7.33 (a series of multiplet peaks, 9H),2.05 (s, 3H). LCMS (ESI) m/e 449 (M+H)⁺.

Synthesis of Amine 4026

To a solution of 0.100 g (0.28 mmol) of amine 54 in 3 mL of MeOH/THF(2:1, with 1% acetic acid) were added 0.024 g (0.25 mmol) of2-furaldehyde and 0.089 g (0.42 mmol) of sodium triacetoxyborohydride atroom temperature. The reaction mixture was allowed to stir at 25° C.until the aldehyde was consumed based on TLC analysis. The solvents ofthe reaction were removed via rotary evaporation, and the residue wasthen purified on a preparative TLC plate to give 26.6 mg of 4026. ¹H NMR(300 MHz, CD₃OD): δ 7.52˜7.26 (a series of multiplet peaks, 10H), 1.87(s, 3H). LCMS (ESI) m/e 438 (M+H)⁺.

Example 52 Synthesis of Amine 4038 Method A

A solution of 8.00 g (115.9 mmol) of isoxazole and 31.30 g (139.1 mmol)of N-iodosuccinimide in 60 ml of trifluoroacetic acid was heated to 50°C. for 6 h. The reaction mixture was cooled and evaporated at 0° C. toremove the majority of trifluoroacetic acid. The residue was thendissolved in 200 ml of diethyl ether, washed sequentially with saturatedNaHCO₃ (40 ml×4), 10% sodium thiosulfate (40 ml×2), and brine (40 ml),dried over MgSO₄, filtered and concentrated to give 16.50 g of thedesired 4-iodoisoxazole product. ¹H NMR (300 MHz, CDCl₃): δ 8.44 (s,1H), 8.29 (s, 1H).

To a solution of 6.80 g (34.8 mmol) of 4-iodoisoxazole in 200 ml of THFat −100° C. was added dropwise 22.9 ml (36.6 mmol) of n-BuLi (1.6 M inhexanes). The reaction mixture was allowed to stir for 30 min. Ethylformate (3.08 ml, 38.4 mmol) was added to the mixture, and the mixturewas stirred further for 30 min at −100° C. Hydrochloric acid (36.60 mlof 1 N HCl in ether) was added at −100° C., and the reaction mixture wasallowed to warm gradually to 25° C. The mixture was diluted with ether(200 ml), washed sequentially with saturated NaHCO₃ (100 ml) and brine(100 ml), dried over MgSO₄, filtered and concentrated (at 0° C.) to give˜2.00 g of the desired isoxazole-4-carbaldehyde (based on estimationfrom ¹H NMR; contaminated with residual EtOH) of suitable purity for usein subsequent reactions. ¹H NMR (300 MHz, CDCl₃): δ 10.01 (s, 1H), 9.05(s, 1H), 8.68 (s, 1H).

A solution of 4.00 g (11.2 mmol) of amine 54, 1.03 g (10.6 mmol) ofisoxazole-4-carbaldehyde, and 4.750 g (22.4 mmol) of NaB(OAc)₃H in 30 mlof DMF with 1.0 ml of acetic acid was stirred at 25° C. for 4 h. Thereaction solvents were removed by rotary evaporation. The residue waspurified by silica gel column chromatography using 5% MeOH in CH₂Cl₂ aseluent to give 1.57 g of amine 4038 plus 1.58 g of the imineintermediate. LCMS (ESI) m/e 439 (M+H)⁺.

Method B

A solution of 1.00 g (5.05 mmol) of isoxazol-4-ylmethyl-carbamic acidtert-butyl ester in 10 ml of 4.0 N HCl in dioxane was stirred at 25° C.for 6 h. The reaction mixture was then diluted with 30 ml of diethylether and filtered. The solid was washed with diethyl ether and dried togive 0.65 g of C-isoxazol-4-yl-methylamine hydrochloride salt ofsuitable purity for use in subsequent reactions. ¹H NMR (300 MHz, DMSO):δ 9.02 (s, 1H), 8.68 (s, 1H), 3.94 (q, J=6, 1H).

A solution of aldehyde 92 (0.150 g, 0.42 mmol),C-isoxazol-4-yl-methylamine hydrochloride salt (0.068 g, 0.51 mmol)obtained above, and NaB(OAc)₃H (0.268 g, 1.26 mmol) in 5 ml of DMF wasstirred at 25° C. for 2 h. The reaction solvent was removed by rotaryevaporation, and the residue was purified by preparative thin-layerchromatography to give 0.160 g of amine 4038. LCMS (ESI) m/e 439 (M+H)⁺.

Example 53 Synthesis of Amine 4215

Scheme 34 depicts the synthesis of amine 401 used in the synthesis ofcompound 4215.

Synthesis of Amine 401

A solution of aldehyde 92 (3.56 g, 10.0 mmol) in anhydrous DMF (20 mL)was treated with a 2 N solution of methylamine in THF (25 mL, 50.0 mmol)and sodium triacetoxyborohydride (3.20 g, 15.0 mmol) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 6 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was quenched with H₂O (40 mL), and theresulting mixture was stirred at room temperature for 30 min. The solidprecipitate was then collected by filtration, washed with H₂O (2×50 mL),and dried in vacuo. This crude material was subsequently purified byflash column chromatography (5-15% MeOH—CH₂Cl₂ gradient elution) toafford amine 401 (2.26 g; 61%) as an off-white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 2.03 (s, 3H, COCH₃), 2.46 (s, 3H, NMe), 3.62 (t, 2H, J=5.4Hz), 3.86 (s, 2H, Ar—CH₂)), 3.96 (dd, 1H, J=6.4, 9.2 Hz), 4.35 (t, 1H,J=9.2 Hz), 4.90-4.99 (m, 1H), 7.58-7.80 (m, 7H, aromatic-H), 8.45 (t,1H, J=5.8 Hz, NHCOCH₃); LCMS (ESI) m/z 372 (M+H)⁺.

Synthesis of Amine 4215

A solution of amine 401 (0.070 g, 0.19 mmol) in methanol (2 mL) andacetic acid (0.020 mL) was treated with quinoline-3-carboxaldehyde(0.033 g, 0.21 mmol) and sodium triacetoxyborohydride (0.080 g, 0.38mmol) and stirred at 23° C. for 2 h. Additional sodiumtriacetoxyborohydride (0.080 g, 0.38 mmol) and acetic acid (0.020 mL)were added, and the reaction mixture was stirred for 16 h. The solventwas removed in vacuo, and the residue was dissolved in THF (3 mL) andacetic acid (0.020 mL) and treated with quinoline-3-carboxaldehyde(0.015 g, 0.095 mmol) and sodium triacetoxyborohydride (0.080 g, 0.38mmol) and stirred for 9 h. Additional sodium triacetoxyborohydride(0.080 g, 0.38 mmol) was added, and the reaction mixture was stirred for60 h. The reaction mixture was diluted with methylene chloride (30 mL)and washed with saturated aqueous sodium bicarbonate (25 mL). Dryingover Na₂SO₄ and evaporation of solvent yielded crude product, which waspurified by flash chromatography (18:1:0.1 methylenechloride:methanol:ammonium hydroxide, 5-10% methanol in 1:1 methylenechloride:ethyl acetate) to afford amine 4215 as a solid (0.030 g, 0.059mmol; 31%). LCMS (ESI) m/z 513 (M+H)⁺.

Example 54 Synthesis of Sulfide 4216 and Sulfoxide 4217

Scheme 35 depicts the synthesis of compounds 4216 and 4217. Benzylchloride 90 is displaced with thiolacetic acid to afford thioacetate402. Hydrolysis of 402 afforded thiol 403 which was alkylated with2-bromomethylpyridine to yield sulfide 4216. Oxidation of 4216 thenprovided sulfoxide 4217.

Synthesis of Chloride 90

Alcohol 51 (3.0 g, 8.4 mmol) was dissolved in CH₂Cl₂ (20 mL) and Hunig'sbase (2 mL). Methanesulfonyl chloride (1.4 mL, 12.6 mmol) was addeddropwise and the resulting solution stirred at rt for 4 h. The mixturewas poured into 100 mL sat. aqueous NaHCO₃ and extracted with CH₂Cl₂(3×50 mL). The combined organic extracts were washed with brine, driedover MgSO₄, filtered, and concentrated to give 3.9 g of an oily yellowsolid. The crude material was purified by silica gel chromatography togive chloride 90 as an off-white solid (2.7 g, 7.2 mmol). LCMS (ESI) m/z377 (M+H)⁺, 418 (M+CH₃CN+H)⁺, 440 (M+CH₃CN+Na)⁺.

Synthesis of Thioester 402

Under an argon atmosphere, thiolacetic acid (1.55 mL, 21.7 mmol) wasadded to a mixture of chloride 90 (4.08 g, 10.8 mmol) and Cs₂CO₃ (3.52g, 10.8 mmol) in DMF (25 mL). The reaction was stirred at roomtemperature for 2 hours. Then 50 mL of water was added. The off-whiteproduct 402 (4.3 g) was collected by filtration in a yield of 96%. LCMS(ESI) m/z 417 (M+H)⁺.

Synthesis of Thiol 403

LiOH (360 mg, 15 mmol) was added to a solution of 402 (4.3 g, 10.3 mmol)in a mixture of THF (50 mL), MeOH (50 mL) and water (20 mL). Afterstirring for 30 minutes at room temperature under argon atmosphere, theinsoluble solid was removed by filtration. The filtrate was diluted withwater (50 mL), concentrated to remove organic solvents, then neutralizedwith 10% HCl. The off-white product 403 (3.5 g) was collected byfiltration in a yield of 91%. LCMS (ESI) m/z 375 (M+H)⁺.

Synthesis of Sulfide 4216

A solution of sulfide 403 (0.20 g, 0.54 mmol) in tetrahydrofuran (1.3mL), methanol (1.3 mL), and dimethylformamide (1.3 mL) was treated withsodium methoxide

(25% in methanol, 0.24 mL, 1.1 mmol) and 2-(bromomethyl)pyridine andstirred at 23° C. for 0.5 h. The reaction mixture was diluted withmethylene chloride (25 mL), washed with water (25 mL), and the waterlayer was extracted with methylene chloride (25 mL). The combinedorganic fractions were dried over Na₂SO₄, and evaporated in vacuo toyield crude product, which was purified by preparative thin-layerchromatography (5% methanol/methylene chloride) to afford 4216 as awhite powder (0.12 g, 0.26 mmol; 48%). LCMS (ESI) m/z 466 (M+H)⁺.

Synthesis of Sulfoxide 4217

A solution of 4216 (0.11 g, 0.23 mmol) in methylene chloride (2.3 mL)was treated with 3-chloroperoxybenzoic acid (0.051 g, 0.23 mmol) andstirred at 23° C. for 15 minutes.

The solvent was evaporated in vacuo and the crude product was purifiedby flash chromatography (5% methanol/methylene chloride) to afford 4217as a white powder (0.093 g, 0.19 mmol; 83%). LCMS (ESI) m/z 482 (M+H)⁺.

Example 55 Synthesis of Compounds 4218-4220 Synthesis of Amine 4218

A solution of amine 54 (0.600 g, 1.68 mmol),1-methyl-indole-3-carboxaldehyde (0.254 g, 1.60 mmol), and NaB(OAc)₃H(0.712 g, 3.36 mmol) in 30 ml of MeOH with a few drops of acetic acidwas stirred at 25° C. for 24 h. The reaction solvents were removed byrotary evaporation. The residue was purified by preparative TLC plate togive 0.070 g of amine 4218. LCMS (ESI) m/z 501 (M+H)⁺.

Synthesis of Amine 4219

A solution of amine 54 (0.060 g (0.17 mmol),tetrahydrofuran-3-carboxaldehyde (0.016 g, 0.16 mmol), and NaB(OAc)₃H(0.071 g, 0.34 mmol) in 5 ml of MeOH with a few drops of acetic acid wasstirred at 25° C. for 6 h. The reaction solvents were removed by rotaryevaporation. The residue was purified by preparative TLC plate to give0.057 g of amine 4219. LCMS (ESI) m/z 442 (M+H)⁺.

Synthesis of Amine 4220

A solution of amine 54 (0.500 g, 1.40 mmol),1,2,3-thiadiazole-4-carboxaldehyde (0.152 g, 1.33 mmol), and NaB(OAc)₃H(0.594 g, 2.80 mmol) in 8 ml of DMF with a few drops of acetic acid wasstirred at 25° C. for 2 h. The reaction solvents were removed by rotaryevaporation. The residue was purified by preparative TLC to give 0.484 gof amine 4220. LCMS (ESI) m/z 492 (M+H)⁺.

Example 56 Synthesis of Compound 4221

A solution of amine 54 (79.0 mg, 0.22 mmol) in anhydrous DMF (3 mL) wastreated with 3-(2-oxo-1,2-dihydro-pyridin-3-yl)-acrylic acid (36.3 mg,0.22 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (62.7 mg, 0.33 mmol) at room temperature, and theresulting reaction mixture was stirred at 25° C. for 12 h. When TLC andLCMS showed that the reaction was complete, the reaction mixture wasconcentrated in vacuo. The residue was directly purified by flash columnchromatography (0-7% MeOH—CH₂Cl₂ gradient elution) to afford amide 4221(45.5 mg; 41%) as a white solid. LCMS (ESI) m/z 505 (M+H)⁺.

Example 57 Synthesis of Amidine 4222

Scheme 36 illustrates the synthesis of amidine 4222. Nitrile 404 andfurfurylamine were heated together in the presence of copper chloride toyield amidine 4222.

Synthesis of Nitrile 404

This compound was made from 4-cyanophenylboronic acid and iodide 50 asdescribed above for the synthesis of alcohol 51.

Synthesis of Amidine 4222

Under an argon atmosphere, a mixture of nitrile 404 (98 mg, 0.28 mmol),furfurylamine (27 mg, 0.28 mmol) and copper (I) chloride (CuCl, 28 mg,0.28 mmol) in DMSO (2 mL) was heated at 80° C. for 48 h. The reactionwas diluted with CH₂Cl₂, washed with saturated Na₂CO₃ and dried undervacuum. The crude product was purified by chromatography (5:1:0.05CH₂Cl₂/MeOH/NH₃.H₂O) to afford 4222 (14 mg; 11%). LCMS (ESI) m/z 451(M+H)⁺.

Example 58 Synthesis of Amide 4223

Scheme 37 illustrates the synthesis of amide 4223. 2,5-Dibromopyridineis converted to activated pyridyl ester 405 which is then treated withhistamine to provide amide 406. The Suzuki coupling of 406 and boronate81 gave the final target amide 4223.

Synthesis of Ester 405

Under an argon atmosphere, triethylamine (0.31 mL, 2.25 mmol) was addedto a mixture of 2,5-dibromopyridine (355 mg, 1.5 mmol), palladiumacetate (16.8 mg. 0.075 mmol), Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 43.4 mg, 0.075 mmol)and N-hydroxysuccinimide (241.5 mg, 2.1 mmol) in DMSO (2 mL). Thesolution was purged with carbon monoxide for 15 min and stirred under acarbon monoxide balloon at 80° C. for 16 h. The reaction mixture wasthen cooled to room temperature, diluted with 20 mL of ethyl acetate andwashed with saturated sodium bicarbonate solution and water. The organicphase was dried over sodium sulfate and evaporated to give crudeproduct. Chromatography on silica gel using hexane:acetone (3:1)provided ester 405 (75 mg; 17%). ¹HNMR (300 MHz, CDCl₃) δ 8.85 (m, 1H),8.06 (m, 2H), 2.90 (s, 4H).

Synthesis of Amide 406

A mixture of active ester 405 (350 mg, 1.17 mmol), histaminedihydrochloride (216 mg, 1.17 mmol) and Et₃N (0.33 mL, 2.34 mmol) inCH₂Cl₂ (5 mL) was stirred at room temperature for 1 h. The reaction waswashed with brine and dried under vacuum. The crude product was purifiedby chromatography (15:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 406 (280 mg;81%). LCMS (ESI) m/z 295 (M+H)⁺.

Synthesis of Amide 4223

Under an argon atmosphere, a mixture of 406 (230 mg, 0.78 mmol),boronate 81 (295 mg, 0.78 mmol), Pd(dppf)₂Cl₂ (19 mg, 0.023 mmol) andK₂CO₃ (323 mg, 2.34 mmol) in 5 mL of a mixture of dioxane/EtOH/H₂O(3:1:1) was heated at 10° C. for 12 h. The reaction was concentrated andthe residue was dissolved in MeOH (2 mL) and CH₂Cl₂ (10 mL). Inorganicsalts were removed by filtration. The filtrate was concentrated andpurified by chromatography (15:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to affordamide 4223 (106 mg; 29%). LCMS (ESI) m/z 467 (M+H)⁺.

Example 59 Synthesis of Amides 4224 and 4225

Scheme 38 illustrates the synthesis of amides 4224 and 4225. Arylbromides 407 and 408 were coupled to boronate 81 to afford 4224 and 4225respectively.

Synthesis of Amide 4224

A mixture of 4-bromobenzoyl chloride (110 mg, 0.5 mmol),1,2,4-oxadiazol-3-yl-methylamine hydrochloride (68 mg, 0.5 mmol), DMF (1drop) and Et₃N (0.33 mL, 2.34 mmol) in CH₂Cl₂ (5 mL) was stirred at roomtemperature for 4 h. The reaction was washed with brine and dried undervacuum to afford crude amide 407. The amide 407 obtained was added to amixture of boronate 81 (189 mg, 0.5 mmol), Pd(dppf)₂Cl₂ (20 mg, 0.025mmol) and K₂CO₃ (207 mg, 1.5 mmol) in 5 mL of dioxane/EtOH/H₂O (3:1:1)under an argon atmosphere. After being heated at 100° C. for 12 h, thereaction was diluted with water and MeOH, and then filtered throughcelite. The filtrate was concentrated to remove organic solvent. Thecrude product was collected by filtration and further purified bychromatography (25:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 4224 (45 mg;32%). LCMS (ESI) m/z 452 (M−H)⁺.

Synthesis of Amide 4225

A mixture of 4-bromobenzoyl chloride (29 mg, 0.132 mmol),1,2,4-thiadiazol-3-yl-methylamine hydrochloride (20 mg, 0.132 mmol), DMF(1 drop) and Et₃N (27 mg, 0.264 mmol) in THF (4 mL) was stirred at roomtemperature for 2 h. The reaction was concentrated, dissolved in CH₂Cl₂,washed with brine and dried under vacuum to afford crude amide 408. Theresultant amide 408 obtained above was added to a mixture of boronate 81(50 mg, 0.132 mmol), Pd(dppf)₂Cl₂ (6 mg, 0.0066 mmol) and K₂CO₃ (55 mg,0.396 mmol) in 2 mL of dioxane/EtOH/H₂O (3:1:1) under an argonatmosphere. After being heated at 100° C. for 12 h, the reaction wasconcentrated, dissolved in EtOAc, washed with brine and dried undervacuum. The crude product was purified by chromatography on silica gel(25:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to afford amide 4225 (30 mg; 48%). LCMS(ESI) m/z 470 (M+H)⁺.

Example 60 Synthesis of Sulfide 4226

Under an argon atmosphere, sodium methoxide (NaOMe, 25% by wt. in MeOH,95 mg, 0.44 mmol) was added to a solution of thiol 403 (75 mg, 0.2 mmol)and epibromohydrin (30 mg, 0.22 mmol) in MeOH (3 mL) and THF (3 mL).After stirring at room temperature for 2 h, the reaction wasconcentrated. The residue was dissolved CH₂Cl₂, washed with brine, driedover MgSO₄ and concentrated under vacuum. The crude product was purifiedby chromatography on silica gel (25:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) toafford sulfide 4226 (55 mg; 61% as a mix of diastereomers). LCMS (ESI)m/z 453 (M+Na)⁺.

Example 61 Synthesis of Amines 4227-4229 Synthesis of Amine 4227

A suspension of aldehyde 92 (107 mg, 0.3 mmol) in anhydrous THF (2 mL)and anhydrous methanol (MeOH, 2 mL) was treated with2-(1H-imidazol-4-yl)-ethylamine (110.0 mg, 0.6) and sodiumtriacetoxyborohydride (127 mg, 0.6 mmol) at room temperature, and theresulting reaction mixture was stirred at room temperature for 6 h. WhenTLC and LCMS showed that the reaction was complete, the reaction mixturewas concentrated in vacuo. This residue was directly purified by flashcolumn chromatography (0-10% MeOH—CH₂Cl₂ gradient elution) to affordamine 4227 (24 mg, 135.3 mg; 18%) as an off-white solid. LCMS (ESI) m/z452 (M+H)⁺.

Synthesis of Amine 4228

A suspension of aldehyde 92 (107 mg, 0.3 mmol) in anhydrous THF (2 mL)and anhydrous methanol (MeOH, 2 mL) was treated with2-(5-methyl-1H-indol-3-yl)-ethylamine hydrochloride (126.0 mg, 0.6 mmol)and sodium triacetoxyborohydride (127 mg, 0.6 mmol) at room temperature,and the resulting reaction mixture was stirred at room temperature for12 h. When TLC and LCMS showed that the reaction was complete, thereaction mixture was concentrated in vacuo. This residue was directlypurified by flash column chromatography (0-10% MeOH—CH₂Cl₂ gradientelution) to afford amine 4228 (32 mg; 21%) as off-white solids. LCMS(ESI) m/z 515 (M+H)⁺.

Synthesis of Amine 4229

A suspension of aldehyde 92 (107 mg, 0.3 mmol) in anhydrous THF (2 mL)and anhydrous methanol (2 mL) was treated with(5-methyl-isoxazol-3-yl)-methylamine (67.0 mg, 0.6 mmol) and sodiumtriacetoxyborohydride (127 mg, 0.6 mmol) at room temperature, and theresulting reaction mixture was stirred at room temperature for 12 h.When TLC and LCMS showed that the reaction was complete, the reactionmixture was concentrated in vacuo. This residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford amine 4229 (34 mg; 25%) as an off-white solid. LCMS (ESI) m/z 453(M+H)⁺.

Example 62 Synthesis of Amines 4230 and 4231

Scheme 39 shows the synthesis of amines 4230 and 4231. Known alcohol 409(see U.S. Pat. Nos. 5,523,403 and 5,565,571) is coupled to4-formylphenylboronic acid to afford alcohol 410 which is then convertedto mesylate 411. Alkylation of mesylate 411 with the appropriatenucleophiles affords biaryl aldehydes 412 and 413 which are transformedto amines 4230 and 4231 respectively by reductive amination chemistry.

Synthesis of Alcohol 410

A suspension of alcohol 409 (5.07 g, 15.0 mmol) in toluene (30 mL) wastreated with 4-formylphenylboronic acid (3.15 g, 21.0 mmol), K₂CO₃ (6.22g, 45.0 mmol), EtOH (10 mL), and H₂O (10 mL) at 25° C., and theresulting mixture was degassed three times under a steady stream ofargon at 25° C. Pd(dppf)₂Cl₂ (370 mg, 0.45 mmol) was subsequently addedto the reaction mixture, and the resulting reaction mixture was degassedthree times again before being warmed to gentle reflux for 2 h. When TLCand LCMS showed the coupling reaction was complete, the reaction mixturewas cooled to room temperature before being treated with H₂O (100 mL).The resulting mixture was then stirred at room temperature for 10 minbefore being cooled to 0-5° C. for 1 h. The solid precipitate wascollected by filtration, washed with H₂O (2×40 mL) and 20% EtOAc/hexane(2×40 mL), and dried in vacuo. The crude alcohol 410 (4.62 g; 98%) wasobtained as a brown solid, which by HPLC and ¹H NMR was found to be ofsuitable purity to be used in subsequent reactions. LCMS (ESI) m/z 316(M+H)⁺.

Synthesis of Mesylate 411

A solution of the crude alcohol 410 (4.2 g, 13.3 mmol) in CH₂Cl₂ (50 mL)was treated with diisopropylethylamine (2.6 g, 3.5 mL, 20.0 mmol) at 25°C., and the resulting mixture was cooled to 0-5° C. before being treateddropwise with methanesulfonyl chloride (1.83 g, 1.25 mL, 16.0 mmol) at0-5° C. The resulting reaction mixture was subsequently stirred at 0-5°C. for 2 h. When TLC and LCMS showed the reaction was complete, thereaction mixture was treated with H₂O (50 mL) at 0-5° C. The mixture wasthen concentrated in vacuo to remove most of the CH₂Cl₂, and theresulting slurry was treated with H₂O (50 mL). The mixture was stirredat room temperature for 10 min before being cooled to 0-5° C. for 30min. The solid precipitate was collected by filtration, washed with H₂O(2×40 mL) and 20% EtOAc/hexane (2×20 mL), and dried in vacuo. The crudemesylate 411 (4.60 g; 88%) was obtained as a brown solid, which by ¹HNMR and HPLC was found to be of suitable purity to be used in subsequentreactions. LCMS (ESI) m/z 394 (M+H)⁺.

Synthesis of Aldehyde 412

A solution of mesylate 411 (393 mg, 0.1 mmol) in anhydrous DMF (4 mL)was treated with 1H-1,2,4-triazole sodium salt (100 mg, 1.1 mmol) atroom temperature, and the resulting reaction mixture was warmed to 40°C. and stirred at 40° C. for 4 h. When TLC and LCMS showed that thereaction was complete, the reaction mixture was concentrated in vacuo.This residue was directly purified by flash column chromatography (0-5%MeOH—CH₂Cl₂ gradient elution) to afford aldehyde 412 (318.4 mg; 87%) asan off-white solid. LCMS (ESI) m/z 367 (M+H)⁺.

Synthesis of Amine 4230

A suspension of aldehyde 412 (90.0 mg, 0.25 mmol) in anhydrous THF (2mL) and anhydrous DMF (2 mL) was treated with C-pyridin-4-yl-methylamine(29.0 mg, 0.27 mmol) and sodium triacetoxyborohydride (106.0 mg, 0.5mmol) at room temperature, and the resulting reaction mixture wasstirred at room temperature for 6 h. When TLC and LCMS showed that thereaction was complete, the reaction mixture was concentrated in vacuo.This residue was directly purified by flash column chromatography (0-5%MeOH—CH₂Cl₂ gradient elution) to afford amine 4230 (47.0 mg; 41%) as anoff-white solid. LCMS (ESI) m/z 459 (M+H)⁺.

Synthesis of Aldehyde 413

A solution of 1-methyl-1H-tetrazole-5-thiol sodium salt (174.0 mg, 1.5mmol) in anhydrous THF (5 mL) was treated with NaH (60% oil dispersionin mineral oil, 60.0 mg, 1.5 mmol) at 0-5° C., and the resultingreaction mixture was stirred at 0-5° C. for 1 h. The mixture was thentreated with mesylate 411 (393.0 mg, 1.0 mmol) and anhydrous DMF (5 mL)at 0-5° C., and the resulting reaction mixture was gradually warmed toroom temperature before being warmed to 40° C. for 4 h. When TLC andLCMS showed that the reaction was complete, the reaction mixture wasconcentrated in vacuo. This residue was directly purified by flashcolumn chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to affordaldehyde 413 (272.6 mg; 66%) as an off-white solid. LCMS (ESI) m/z 414(M+H)⁺.

Synthesis of Amine 4231

A suspension of aldehyde 413 (100.0 mg, 0.24 mmol) in anhydrous THF (2mL) and anhydrous DMF (2 mL) was treated with C-pyridin-4-yl-methylamine(29.0 mg, 0.27 mmol) and sodiumborohydride (15.0 mg, 0.24 mmol) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 12 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was concentrated in vacuo. This residuewas directly purified by flash column chromatography (0-5% MeOH—CH₂Cl₂gradient elution) to afford amine 4231 (44.0 mg; 36%) as an off-whitesolid. LCMS (ESI) m/z 506 (M+H)⁺.

Example 63 Synthesis of Amine 4233

Scheme 40 shows the synthesis of isoxadiazole 4233.BOC-Aminoacetonitrile was converted to hydroxyamidine 414 which was thencyclyzed to isoxadiazole 415. Reductive amination of 415 with aldehyde92 afforded amine 4233.

Synthesis of Hydroxyamidine 414

To a solution of BOC-aminoacetonitrile (6.0 g, 38 mmol) in EtOH (60 mL)was added 50% aq. hydroxylamine (4.5 mL, 77 mmol) and the mixture wasrefluxed for 5 h. The solvents were evaporated and the residueredissolved in CH₂Cl₂ (100 mL), dried over Na₂SO₄ and again evaporated,yielding hydroxyamidine 414 (7 g; 96%). ¹H-NMR, (300 MHz, CDCl₃) δ5.43-5.39 (m 1H), 5.12-5.03 (m, 3H), 3.75 (d, J=5 Hz, 2H), 1.46 (s, 9H).

Synthesis of Isoxadiazole 415

To a solution of 414 (2.8 g, 14.7 mmol) in CH₂Cl₂ (45 mL) was added Et₃N(4.1 mL, 29.5 mmol), formic acid (0.72 mL, 19.2 mmol), EDCI (4.24 g, 22mmol), and DMAP (89 mg, 0.7 mmol). The mixture was stirred at roomtemperature for 3 h, evaporated to ca. 15 mL, diluted with ethyl acetate(50 mL), washed with 1M citric acid (20 mL), water (2×20 mL), brine(1×20 mL), dried over Na₂SO₄ and the solvent evaporated. The cruderesidue was dissolved in pyridine (11 mL) and stirred at 105° C. for 4.5h, poured into 1M citric acid-ice (100 mL) and extracted with ethylacetate (2×50 mL). The combined organic layer was washed with water(2×15 mL), brine (1×15 mL), dried over Na₂SO₄ and the solventevaporated. The residue was dissolved in 4M HCl in dioxane (7 mL). Themixture was stirred at room temperature for 2 h and then evaporated anddiluted with ether (3 mL). The solution was filtered and the solid waswashed with ether (2×5 mL) and dried under high vacuum to yield 415 (855mg; 83%). ¹H-NMR, (300 MHz, d₆-DMSO) δ 9.6 (s, 1H), 8.77 (br s, 3H),4.09 (m, 2H).

Synthesis of Amine 4233

Amine 4233 was synthesized from 415 and aldehyde 92 using the sameconditions described in Example 53 for the synthesis of amine 401 fromaldehyde 92. LCMS (ESI) m/z 441 (M+H)⁺.

Example 64 Synthesis of Amine 4234

Scheme 41 depicts the synthesis of amine 4234. Known ester 416 (LiebigsAnnalen der Chemie 1979, 1370) was reduced to alcohol 417 which wasmanipulated to amine salt 418 via standard chemistry. Reductiveamination of 418 with aldehyde 19 yielded amine 4234.

Synthesis of Alcohol 417

To a solution of the oxazole 416 (500 mg, 4.4 mmol) in MeOH (20 mL) wasadded sodium borohydride (NaBH₄, 540 mg, 17.5 mmol). The mixture wasstirred at room temperature for 2 h, then NaBH₄ (540 mg, 17.5 mmol) wasadded. After 1 h an additional amount of NaBH₄ (270 mg, 9.0 mmol) wasadded. After stirring for 2 h, the mixture was quenched with 5% Na₂CO₃(2 mL) and evaporated. The crude residue was purified on silica geleluting with ether, yielding 417 as a clear oil (300 mg; 86%). ¹H-NMR,(300 MHz, CDCl₃) δ 7.82 (s, 1H), 7.57 (s, 1H), 4.57 (s, 2H).

Synthesis of Amine Hydrochloride 418 Alcohol 417 was converted to aminesalt 418 following the procedure described above to make amine 54 fromalcohol 51. The crude material was taken up HCl in dioxane and thentriturated with ether to isolate the salt as was described above foramine salt 415.

Synthesis of Amine 4234

This amine was synthesized from 418 and aldehyde 92 using the sameconditions described above for the synthesis of amine 401 from aldehyde92. LCMS (ESI) m/z 439 (M+H)⁺.

Example 65 Synthesis of Amine 4235

Scheme 42 depicts the synthesis of amine 4235 from aldehyde 419 andamine salt 418.

Synthesis of Aldehyde 419

Aldehyde 419 was synthesized from 5-bromo-pyridine-2-carboxaldehyde andboronate ester 81 as described above for the synthesis of amide 4223.

Synthesis of Amine 4235

Amine 4235 was synthesized from aldehyde 419 and amine salt 418 usingthe same conditions described in Example 53 for the synthesis of amine401 from aldehyde 92. LCMS (ESI) m/z 440 (M+H)⁺.

Example 66 Synthesis of Compound 4208

Scheme 43 depicts the synthesis of compound 4208.

To a solution of tert-Butyl N-(2-oxoethyl)carbamate (4.0 g, 25.1 mmol)in MeOH (80 mL) was added K₂CO₃ (10.4 g, 75.4 mmol) followed bytosylmethylisocyanide (TOSMIC, 4.91 g, 25.1 mmol). The suspension wasrefluxed for 1 h and then evaporated. The residue was poured intoice-water (100 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were washed with water (2×20 mL), brine (lx 20mL), dried over Na₂SO₄ and evaporated. The residue was purified onsilica gel eluting with hexanes/ethyl acetate 1:1, yielding a faintyellow oil which was directly dissolved in 4 M HCl in dioxane (15 mL),stirred for 45 min., and evaporated. The residue was crystallized withether (10 mL) and filtered, yielding amine 420 (1.50 g, 42%). ¹H-NMR,(300 MHz, d-DMSO δ 8.73 (br.s 3H), 8.48 (s, 1H), 7.28 (s, 1H), 4.20-4.12(m, 2H).

Compound 4208 was synthezised from amine 420 and aldehyde 92 using thesame conditions described in Example 53 for the synthesis of amine 401from aldehyde 92. LCMS (ESI): 439.1 (M+H)⁺.

Example 67 Synthesis of Compound 4136

A solution of amine 54 (0.070 g, 0.20 mmol) in DMF (1.0 ml) was treatedwith triethylamine (0.055 ml, 0.40 mmol) and 2-phthalimidoethanesulfonylchloride (0.059 mg, 0.22 mmol) and stirred at 23° C. for 3.5 h.Additional 2-phthalimidoethanesulfonyl chloride (0.081 mg, 0.30 mmol)and triethylamine (0.087 ml, 0.63 mmol) were added, and the reactionmixture was stirred for 16 h. The reaction mixture was diluted withmethylene chloride (20 ml), washed with 1 M hydrochloric acid (20 ml),and washed with saturated aqueous sodium bicarbonate (20 ml). Dryingover Na₂SO₄ and evaporation of solvent yielded crude product, which waspurified by flash chromatography (2.5-5% methanol in 1:1 methylenechloride/ethyl acetate) to afford compound 4136 (0.082 g, 0.14 mmol,70%). MS (ESI): 617 (M+Na)⁺.

Example 68 Synthesis of Compound 4239

Scheme 44 depicts the synthesis of compound 4208.

Synthesis of Azide 422

To a solution of bromoacetic acid (1.0 g, 2.8 mmol) and1-hydroxybenzotriazole hydrate (HOBT, 0.44 g, 3.4 mmol) in DMF (15 mL)was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC.HCl, 0.66 g, 3.4 mmol) and amine 54 (0.45 g, 3.2 mmol) in a rapidsuccession. The resulting mixture was stirred at room temperatureovernight. The solvent was evaporated and the crude product wassuspended in water (about 40 mL). The suspension was filtered and theresidue was washed with water, diethyl ether (about 50 mL) and dried invacuo to give analytically pure compound 421 as white solid inquantitative yield.

Compound 421 was dissolved in DMF (10 mL) and NaN₃ (0.55 g, 8.0 mmol)was added. The mixture was heated at 60° C. overnight and solventevaporated off. The crude was suspended in water (about 40 mL),filtered, and the residue was washed with water, diethyl ether (about 50mL) and dried in vacuo to give analytically pure azide 422 as whitesolid (0.97 g, 69.3%). LCMS (ESI): 441 (M+H)⁺.

Synthesis of Triazole 4239

Azide 422 (0.25 g, 0.57 mmol) and TMS-acetylene (0.28 g, 2.84 mmol) weredissolved in DMF (5 mL) and the mixture was heated at 90° C. for 24 hunder an argon atmosphere. The solvent was evaporated off, leaving asolid residue. The residue was suspended in water, filtered and dried invacuo. To the solution of this residue in THF (5 mL) was added IM TBAFin THF (1.14 mL) and acetic acid (0.04 mL, 0.57 mmol), and the mixturewas stirred at room temperature overnight, after which time TLC showed acomplete consumption of the starting material. The solvent wasevaporated off and the crude was suspended in diethyl ether (about 40mL). The suspension was filtered, and the residue was washed insuccession with CH₂Cl₂ (about 50 mL), 10% CH₃CN in diethyl ether (about50 mL), diethyl ether (about 20 mL). The residue was air dried to giveanalytically pure triazole 4239 as white solid (0.238 g, 89.6%). LCMS(ESI): 467.1 (M+H)⁺.

Example 69 Synthesis of Compound 4252

A solution of the methanesulfonic acid5-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridin-2-ylmethylester 106 (220 mg, 0.5 mmol) in DMF (4.0 mL) was treated withC-isoxazol-4-yl-methylamine (68 mg, 0.5 mmol, 1.0 equiv) at roomtemperature, and the resulting reaction mixture was warmed to 60° C. andstirred for 6 hours. When TLC and MS showed the reaction to be complete,the reaction mixture was concentrated in vacuo, and the residue wasdirectly purified by column chromatography (0-5% MeOH/CH₂Cl₂ gradientelution) to afford the desiredN-{3-[3-Fluoro-4-(6-{[(isoxazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide4252 (22 mg, 10%) as off-white solids. LCMS (EI): 440 (M⁺+H).

Example 70 Synthesis of Compound 4262

Scheme 45 depicts the synthesis of compound 4262.

To a solution of 0.060 g (0.17 mmol) of aldehyde 92 and 0.056 g (0.25mmol) of the HCl salt of amine 423 in 3 ml of DMF was added 0.071 g(0.34 mmol) of NaB(OAc)₃H. The reaction mixture was stirred at 25° C.for 2 h. The DMF was removed, and the residue was purified bypreparative TLC to give 0.041 g of compound 424. MS (M+1): 525.

To a solution of 0.012 g (0.023 mmol) of 424 and 0.03 ml (0.027 mmol) ofTBAF (1 M in THF) in 4 ml of CH₂Cl₂ was added a few drops of aceticacid, and the mixture was stirred at 0° C. for 4 h. The reactionsolvents were removed by rotary evaporation, and the residue waspurified by preparative TLC to give 0.008 g of compound 4262. MS (M+1):489.

Example 71 Synthesis of Triazole 4276

Scheme 46 depicts the synthesis of triazole 4276.

Synthesis of Alkyne 425

To a solution of chloride 90 (2 g, 5.3 mmol) and Hunig's base(diisopropylethylamine, 1.7 mL, 10 mmol) in DMF (15 mL) was added asolution of N-methyl propargylamine (0.55 g mg, 8.0 mmol) in DMF (1 mL).After stirring at room temperature for 16 h, the DMF was removed invacuo. The crude product was purified by preparative thin layerchromatography (10:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 2.05 g ofalkyne 425 in a yield of 95%. MS (ESI): 410.1 (100%) (M+Na)⁺.

Synthesis of Compound 4276

A mixture of alkyne 425 (1.8 g, 4.4 mmol), sodium azide (0.43 g, 6.6mmol), ammonium chloride (0.35 g, 6.6 mmol), copper(I) iodide (84 mg,0.44 mmol) and Hunig's base (3.5 mL, 20 mmol) in DMF (10 mL) was heatedunder argon atmosphere at 80° C. for 48 h. The DMF was removed in vacuo,and the residue was dissolved in MeOH (5 mL), CH₂Cl₂ (50 mL), conc.ammonium hydroxide (20 mL) and saturated ammonium chloride solution (20mL). After stirring at room temperature for 2 h, the organic phase wasseparated, washed with saturated NH₄Cl solution and water, dried overMgSO₄, and concentrated. The crude product was purified by preparativethin layer chromatography (10:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 1.75mg of triazole 4276 in a yield of 88%. MS (ESI): 453.1 (100%) (M+H)⁺,475.2 (M+Na)⁺.

Example 72 Synthesis of Triazole 4278

Scheme 47 depicts the synthesis of triazole 4278.

Synthesis of Alkyne 426

A mixture of amine 54 (422 mg, 1.18 mmol), butyn-3-yl tosylate (265 mg,1.18 mmol), Hunig's base (diisopropylethylamine, 0.2 mL, 1.15 mmol) andpotassium iodide (17 mg, 0.1 mmol) in DMF (5 mL) was heated at 70° C. 15h. The DMF was removed in vacuo. The residue was dissolved in a mixedsolvent of THF (10 mL) and water (2 mL), K₂CO₃ (276 mg, 2 mmol), andthen di-tert-butyl dicarbonate (218 mg, 1 mmol) was added. The reactionwas stirred at room temperature for 12 h, and the THF was removed invacuo. 40 mL of EtOAc was added and the solution was washed with water,dried over MgSO₄ and concentrated. The crude product was purified bypreparative thin layer chromatography (15:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) toafford 210 mg of alkyne 426 in a yield of 22%. MS (ESI): 410.1, 532.1(M+Na)⁺, 573.1 (100%).

Synthesis of Triazole 427

A mixture of alkyne 426 (150 mg, 0.29 mmol), sodium azide (29 mg, 0.44mmol), ammonium chloride (24 mg, 0.44 mmol), copper(I) iodide (56 mg,0.29 mmol) and Hunig's base (0.26 mL, 1.5 mmol) in DMF (3 mL) was heatedunder argon atmosphere at 80° C. for 24 h. The DMF was removed in vacuo,and the residue was dissolved in CH₂Cl₂ and conc. ammonium hydroxidesolution. The organic phase was separated, washed with saturated NH₄Clsolution and water, dried over MgSO₄, and concentrated. The crudeproduct was purified by preparative thin layer chromatography (15:1:0.05CH₂Cl₂/MeOH/NH₃.H₂O) to afford 155 mg of triazole 427 in a yield of 95%.MS (ESI): 453.1 (100%), 575.1 (M+Na)⁺.

Synthesis of Compound 4278

To a solution of triazole 427 (155 mg, 0.28 mmol) in CH₂Cl₂ (5 mL) andMeOH (1 mL) was added 2 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 15 h, the reaction was concentrated andwashed with EtOAc/MeOH to give 130 mg of compound 4278 in a yield of95%. MS (ESI): 453.1.1 (100%) (M+H)⁺.

Example 73 Synthesis of Compounds 4316 and 4314 Synthesis of Morpholine4316

Scheme 48 depicts the synthesis of morpholine 4316.

Known bromide 428 was synthesized from morpholine and bromoacetylbromide as reported in the literature (Thompson, W. J. et al. J. Med.Chem. 1992, 35, 1685). To a solution of amine 54 (86 mg, 0.23 mmol) in amixture of methyl alcohol (2 mL), methylene chloride (2 mL) and Hunig'sbase (2 mL) was added bromide 428 (32 mg, 0.23 mmol) at 0° C. Thereaction mixture was warmed to room temperature and heated over an oilbath at 80° C. for 18 h. The solution was concentrated and purified byflash chromatography over silica gel (14:1:0.05 CH₂Cl₂/MeOH: NH₄OH) toyield 66 mg of compound 4316. ¹HNMR (300 MHz, CD₃OD): δ 7.50-7.22 (m,7H), 4.77-4.69 (m, 1H), 4.06 (t, J=9 Hz, 1H), 3.77 (dd, J=6, 3 Hz, 1H),3.70 (s, 1H), 3.55-3.46 (m, 8H), 3.39-3.36 (m, 3H), 3.34-3.30 (m, 2H),1.86 (s, 3H). LCMS (ESI) m/e 485 (M+H)⁺.

Synthesis of Piperazine 4314

Scheme 49 depicts the synthesis of piperazine 4314.

Bromide 429 was synthesized from tert-Butyl 1-piperazine carboxylate andbromoacetyl bromide following literature procedures (Thompson, W. J. etal. J. Med. Chem. 1992, 35, 1685). ¹HNMR (300 MHz, CDCl₃): δ 3.86 (s,2H), 3.61-3.41 (m, 8H), 1.46 (s, 9H). Compound 430 was synthesized fromamine 54 and bromide 429 using the same procedure as described forcompound 4316. LCMS (ESI) m/e 584 (M+H)⁺. A solution of 430 (50 mg,0.085 mmol) in CH₂Cl₂-CF₃COOH (1:1, 4 mL) was stirred at 0° C. for 1 h.The reaction mixture was concentrated and the crude product afterpurification (7:1:0.05 CH₂Cl₂/MeOH/NH₄OH) afforded 35 mg of compound4314. ¹HNMR (300 MHz, CD₃OD): δ 7.51-7.23 (m, 7H), 4.73-4.67 (m, 1H),4.07 (t, J=9 Hz, 1H), 3.75 (dd, J=8, 3 Hz, 1H), 3.73 (s. 2H), 3.48-3.41(m, 6H), 3.24 (s, 2H), 3.21-3.19 (m, 2H), 2.75-2.65 (m, 4H), 1.87 (s,3H). LCMS (ESI) m/e 484 (M+H)⁺.

Example 74 Synthesis of Triazole 5001

Scheme 50 depicts the synthesis of triazole 5001.

Synthesis of Triazole 501

A mixture of 1H-1,2,3-triazole-5-thiol sodium salt 502 (246 mg, 2 mmol)and 2-(Boc-amino)ethyl bromide 503 (448 mg, 2 mmol) in DMF (2 mL) wasstirred at room temperature for 2 h. 50 mL of EtOAc was added and thesolution was washed with water, dried over MgSO₄ and concentrated toafford 458 mg of triazole 501 as colorless oil in a yield of 94%. MS(ESI): 267.0 (100%) (M+Na)⁺.

Synthesis of Triazole 504

To a solution of triazole 501 (458 mg, 1.88 mmol) in CH₂Cl₂ (10 mL) andMeOH (2 mL) was added 4 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 2 h, the reaction was concentrated todryness. The residue was dissolved in DMF (7 mL) and then chloride 90(377 mg, 1 mmol) and Hunig's base (diisopropylethylamine, 0.8 mL, 4.6mmol) were added. The solution was heated at 70° C. for 3 h. The DMF wasremoved in vacuo, and the residue was dissolved in a mixed solvent ofTHF (10 mL) and water (2 mL). K₂CO₃ (414 mg, 3 mmol) and di-tert-butyldicarbonate (545 mg, 2.5 mmol) were then added, and the reaction wasstirred at room temperature for 12 h. The THF was removed in vacuo, 50mL of EtOAc was added, and the solution was washed with water, driedover MgSO₄ and concentrated. The crude product was purified bypreparative thin layer chromatography (15:1:0.1 CH₂Cl₂/MeOH/NH₃.H₂O) toafford 192 mg of triazole 504 in a yield of 33%. MS (ESI): 485.1 (100%),607.2 (M+Na)⁺.

Synthesis of Compound 5001

To a solution of triazole 504 (192 mg, 0.33 mmol) in CH₂Cl₂ (10 mL) andMeOH (2 mL) was added 4 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 12 h, the reaction was concentrated andwashed with EtOAc/MeOH to give 150 mg of triazole 5001 in a yield of94%. MS (ESI): 485.1 (100%) (M+H)⁺, 507.2 (M+Na)⁺.

Example 75 Synthesis of Triazole 5002

Scheme 51 depicts the synthesis of triazole 5002.

Synthesis of Triazole 505

A mixture of 1H-1,2,3-triazole-5-thiol sodium salt 502 (246 mg, 2 mmol)and 2-(BOC-amino)propyl bromide 506 (476 mg, 2 mmol) in DMF (2 mL) wasstirred at room temperature for 1 h. 50 mL of EtOAc was added and thesolution was washed with water, dried over MgSO₄ and concentrated toafford 508 mg of triazole 505 as colorless oil in a yield of 98%. MS(ESI): 281.1 (100%, (M+Na)⁺).

Synthesis of Triazole 507

To a solution of triazole 505 (365 mg, 1.36 mmol) in CH₂Cl₂ (10 mL) andMeOH (2 mL) was added 4 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 2 h, the reaction was concentrated todryness. The residue was dissolved in DMF (5 mL) and then chloride 90(377 mg, 1 mmol) and Hunig's base (diisopropylethylamine, 0.52 mL, 3mmol) were added. The solution was heated at 50° C. for 10 h. The DMFwas removed in vacuo and the residue was purified by preparative thinlayer chromatography (10:1:0.1 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 230 mg ofcrude triazole 5002 (90% pure, MS (ESI): 499.1 (100%) (M+H)⁺).

The free base of 5002 was dissolved in a mixed solvent of THF (10 mL)and water (2 mL), and K₂CO₃ (138 mg, 1 mmol) and di-tert-butyldicarbonate (207 mg, 0.95 mmol) were then added. The reaction wasstirred at room temperature for 12 h. The THF was removed in vacuo. 50mL of EtOAc was added and the solution was washed with water, dried overMgSO₄ and concentrated. The crude product was purified by preparativethin layer chromatography (15:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 220mg of triazole 507 in a yield of 37%. MS (ESI): 499.3 (100%), 621.1(M+Na)⁺.

Synthesis of Compound 5002

To a solution of 507 (98 mg, 0.16 mmol) in CH₂Cl₂ (5 mL) and MeOH (1 mL)was added 2 mL of HCl solution (4.0 M in dioxane). After stirring atroom temperature for 12 h, the reaction was concentrated and washed withEtOAc/MeOH to give 78 mg of compound 5002 in a yield of 95%. MS (ESI):499.1 (100%, (M+H)⁺).

Example 76 Synthesis of Triazole 5007

Scheme 52 depicts the synthesis of triazole 5007.

To a solution of triazole 501 (488 mg, 2 mmol) in CH₂Cl₂ (10 mL) andMeOH (2 mL) was added 4 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 2 h, the reaction was concentrated todryness. The residue was dissolved in DMF (5 mL) and then chloride 123(541 mg, 1.4 mmol) and diisopropylethylamine (0.7 mL, 4 mmol) wereadded. The solution was heated at 50° C. for 18 h. The DMF was removedin vacuo and the residue was purified by preparative thin layerchromatography (10:1:0.15 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 250 mg ofcompound 5007 in a yield of 36%. MS (ESI): 495.0 (100%) (M+H)⁺.

The free base of compound 5007 was dissolved in CH₂Cl₂ (5 mL) and MeOH(5 mL). 2 mL of HCl solution (4.0 M in dioxane) was added at 0° C. Afterstirring at room temperature for 1 h, the reaction was concentrated,washed with EtOAc/MeOH to give 260 mg of the HCl salt compound 5007 in ayield of 97%. MS (ESI): 495.1 (100%) (M+H)⁺.

Example 77 Synthesis of Triazole 5005

Scheme 53 depicts the synthesis of triazole 5005.

Synthesis of Triazole 508

To a solution of 1H-1,2,4-triazole-3-thiol 509 (202 mg, 2 mmol) and2-(BOC-amino)ethyl bromide 503 (448 mg, 2 mmol) in THF (5 mL) and MeOH(2 mL) was added a solution of NaOMe in MeOH (25% wt., 432 mg, 2 mmol).After stirring at room temperature for 2 h, 50 mL of EtOAc was added,and the solution was washed with water, dried over MgSO₄ andconcentrated to afford 464 mg of triazole 508 as colorless oil in ayield of 95%. MS (ESI): 266.8 (100%) (M+Na)⁺.

Synthesis of Triazole 510

To a solution of triazole 508 (366 mg, 1.5 mmol) in CH₂Cl₂ (10 mL) andMeOH (2 mL) was added 4 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 3 h, the reaction was concentrated todryness. The residue was dissolved in DMF (5 mL) and then chloride 90(377 mg, 1 mmol) and Hunig's base (diisopropylethylamine, 0.7 mL, 4mmol) were added. The solution was heated at 50° C. for 12 h. The DMFwas removed in vacuo and the residue was purified by preparative thinlayer chromatography (10:1:0.15 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 250 mg ofcrude compound 5005 (85% pure, MS (ESI): 485.1 (100%) (M+H)⁺)).

The crude 5005 was dissolved in a mixed solvent of THF (10 mL) and water(2 mL), and then K₂CO₃ (276 mg, 2 mmol) and di-tert-butyl dicarbonate(218 mg, 1 mmol) were added. The reaction was stirred at roomtemperature for 12 h. The THF was removed in vacuo. 50 mL of EtOAc wasadded and the solution was washed with water, dried over MgSO₄ andconcentrated. The crude product was purified by preparative thin layerchromatography (15:1:0.1 CH₂Cl₂/MeOH/NH₃.H₂O) to afford 150 mg of 510 ina yield of 26%. MS (ESI): 485.1 (100%), 607.1 (M+Na)⁺.

Synthesis of Compound 5005

To a solution of triazole 510 (150 mg, 0.26 mmol) in CH₂Cl₂ (10 mL) andMeOH (2 mL) was added 2 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 12 h, the reaction was concentrated andwashed with EtOAc/MeOH to give 120 mg of compound 5005 in a yield of89%. MS (ESI): 485.1 (100%, (M+H)⁺), 507.0 (M+Na)⁺.

Example 78 Synthesis of 5011

Scheme 54 depicts the synthesis of triazole 5011.

Synthesis of Compound 511

A mixture of amine 54 (714 mg, 2 mmol), 2R-(−)-glycidyl tosylate 512(456 mg, 2 mmol), N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) andpotassium iodide (33 mg, 0.2 mmol) in DMF (5 mL) was heated at 70° C.for 1 h. The reaction was diluted with 50 mL of EtOAc. The solution waswashed with water, dried over MgSO₄ and concentrated. The crude productwas purified by preparative thin layer chromatography (10:1:0.1CH₂Cl₂/MeOH/NH₃.H₂O) to afford 350 mg of compound 511 in a yield of 42%.MS (ESI): 414.1 (100%), 436.0 (M+Na)⁺.

Synthesis of Compound 513

To a solution of compound 511 (160 mg, 0.39 mmol) in THF (10 mL) and DMF(1 mL) was added di-tert-butyl dicarbonate (138 mg, 0.63 mmol),triethylamine (0.2 mL, 1.4 mmol) and N,N-dimethylaminopyridine. Thereaction was stirred at room temperature for 1 h, and THF was removed invacuo. 40 mL of EtOAc was added and the solution was washed with water,dried over MgSO₄ and concentrated. The crude product was purified bypreparative thin layer chromatography (15:1:0.1 CH₂Cl₂/MeOH/NH₃.H₂O) toafford 138 mg of compound 513 in a yield of 70%. MS (ESI): 514.1 (100%)(M+H)⁺, 536.1 (M+Na)⁺.

Synthesis of Compound 514

To a solution of compound 513 (120 mg, 0.23 mmol) and LiClO₄ (27 mg,0.25 mmol) in acetonitrile (2 mL) was added 1H-1,2,4-triazole-3-thiol509 (24 mg, 0.23 mmol). The reaction was heated at 100° C. for 6 daysand concentrated to dryness. The crude product was purified bypreparative thin layer chromatography (15:1:0.1 CH₂Cl₂/MeOH/NH₃.H₂O) toafford 75 mg of compound 514 in a yield of 53%. MS (ESI): 515.1 (100%),615.1 (M+H)⁺.

Synthesis of Compound 5011

To a solution of compound 514 (75 mg, 0.12 mmol) in CH₂Cl₂ (5 mL) andMeOH (1 mL) was added 1 mL of HCl solution (4.0 M in dioxane). Afterstirring at room temperature for 24 h, the reaction was concentrated andwashed with EtOAc/MeOH to give 62 mg of 5011 in a yield of 94%. MS(ESI): 515.1 (100%) (M+H)⁺.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein: A is selected from the group consisting of: phenyl, pyridyl,pyrazinyl, pyrimidinyl, and pyridazinyl; B is selected from the groupconsisting of: phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;Het-CH₂—R³ is selected from the group consisting of:

M is selected from the group consisting of: a) saturated, unsaturated,or aromatic C₃₋₁₄ carbocycle, and b) saturated, unsaturated, or aromatic3-14 membered heterocycle containing one or more heteroatoms selectedfrom the group consisting of nitrogen, oxygen, and sulfur, wherein a) orb) optionally is substituted with one or more R⁵ groups; M-L is selectedfrom the group consisting of: a) M-X, b) M-L¹, c) M-L¹-X, d) M-X-L², e)M-L¹-X-L², f) M-X-L¹-X-L², g) M-L¹-X-L²-X, h) M-X—X—, i) M-L¹-X—X—, j)M-X—X-L², and k) M-L-X—X-L², wherein X, at each occurrence,independently is selected from the group consisting of: a) —O—, b)—NR⁴—, c) —N(O)—, d) —N(OR⁴)—, e) —S(O)_(p)—, f) —SO₂NR⁴—, g) —NR⁴SO₂—,h) —NR⁴—N═, i) ═N—NR⁴—, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n)—NR⁴—NR⁴—, o) —NR⁴C(O)O—, p) —OC(O)NR⁴—, q) —NR⁴C(O)NR⁴— r)—NR⁴C(NR⁴)NR⁴—, and s)

L¹ is selected from the group consisting of: a) C₁₋₆ alkyl, b) C₂₋₆alkenyl, and c) C₂₋₆ alkynyl, wherein any of a)-c) optionally issubstituted with one or more R⁵ groups; and L² is selected from thegroup consisting of: a) C₁₋₆ alkyl, b) C₂₋₆ alkenyl, and c) C₂₋₆alkynyl, wherein any of a)-c) optionally is substituted with one or moreR⁵ groups; R¹, at each occurrence, independently is selected from thegroup consisting of: a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN,h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴,n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)—C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w)—OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —NR⁴C(NR⁴)NR⁴R⁴, aa)—S(O)_(p)R⁴, bb) —SO₂NR⁴R⁴, and cc) R⁴; R², at each occurrence,independently is selected from the group consisting of: a) F, b) Cl, c)Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k)—C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p)—NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u)—C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y)—NR⁴C(S)NR⁴R⁴, z) —NR⁴C(NR⁴)NR⁴R⁴, aa) —S(O)_(p)R⁴, bb) —SO₂NR⁴R⁴, andcc) R⁴; R³ is selected from the group consisting of: a) —OR⁴, b) —NR⁴R⁴,c) —C(O)R⁴, d) —C(O)OR⁴, e) —OC(O)R⁴, f) —C(O)NR⁴R⁴, g) —NR⁴C(O)R⁴, h)—OC(O)NR⁴R⁴, i) —NR⁴C(O)OR⁴, j) —NR⁴C(O)NR⁴R⁴, k) —C(S)R⁴, l) —C(S)OR⁴,m) —OC(S)R⁴, n) —C(S)NR⁴R⁴, o) —NR⁴C(S)R⁴, p) —OC(S)NR⁴R⁴, q)—NR⁴C(S)OR⁴, r) —NR⁴C(S)NR⁴R⁴, s) —NR⁴C(NR⁴)NR⁴R⁴, t) —S(O)_(p)R⁴, u)—SO₂NR⁴R⁴, and v) R⁴; R⁴, at each occurrence, independently is selectedfrom the group consisting of: a) H, b) C₁₋₆ alkyl, c) C₂₋₆ alkenyl, d)C₂₋₆ alkynyl, e) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle,f) 3-14 membered saturated, unsaturated, or aromatic heterocyclecomprising one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, g) —C(O)—C₁₋₆ alkyl, h) —C(O)—C₂₋₆alkenyl, i) —C(O)—C₂₋₆ alkynyl, j) —C(O)—C₃₋₁₄ saturated, unsaturated,or aromatic carbocycle, k) —C(O)-3-14 membered saturated, unsaturated,or aromatic heterocycle comprising one or more heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C₁₋₆alkyl, m) —C(O)O—C₂₋₆ alkenyl, n) —C(O)O—C₂₋₆ alkynyl, o) —C(O)O—C₃₋₁₄saturated, unsaturated, or aromatic carbocycle, and p) —C(O)O-3-14membered saturated, unsaturated, or aromatic heterocycle comprising oneor more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, wherein any of b)-p) optionally is substituted withone or more R⁵ groups; R¹, at each occurrence, is independently selectedfrom the group consisting of: a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g)═NR⁶, h) ═NOR⁶, i) ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l) —CN, m) —NO₂, n)—NR⁶R⁶, o) —C(O)R⁶, p) —C(O)OR⁶, q) —OC(O)R⁶, r) —C(O)NR⁶R⁶, s)—NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u) —NR⁶C(O)OR⁶, v) —NR⁶C(O)NR⁶R⁶, w)—C(S)R⁶, x) —C(S)OR⁶, y) —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa) —NR⁶C(S)R⁶, bb)—OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶, ee) —NR⁶C(NR⁶)NR⁶R⁶,ff) —S(O)_(p)R⁶, gg) —SO₂NR⁶R⁶, and hh) R⁶; R⁶, at each occurrence,independently is selected from the group consisting of: a) H, b) C₁₋₆alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, f) 3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, g)—C(O)—C₁₋₆ alkyl, h) —C(O)—C₂₋₆ alkenyl, i) —C(O)—C₂₋₆ alkynyl, j)—C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, k)—C(O)-3-14 membered saturated, unsaturated, or aromatic heterocyclecomprising one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, l) —C(O)O—C₁₋₆ alkyl, m) —C(O)O—C₂₋₆alkenyl, n) —C(O)O—C₂₋₆ alkynyl, o) —C(O)O—C₃₋₁₄ saturated, unsaturated,or aromatic carbocycle, and p) —C(O)O-3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur,wherein any of b)-p) optionally is substituted with one or more R⁷groups; R⁷, at each occurrence, independently is selected from the groupconsisting of: a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h)═NOR⁸, i) ═N—NR⁸R⁸, j) —CF₃, k) —OR⁸, l) —CN, m) —NO₂, n) —NR⁸R⁸, o)—C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r) —C(O)NR⁸R⁸, s) —NR⁸C(O)R⁸, t)—OC(O)NR⁸R⁸, u) —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w) —C(S)R⁸, x) —C(S)OR⁸,y) —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa) —NR⁸C(S)R⁸, bb) —OC(S)NR⁸R⁸, cc)—NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸, ee) —NR⁸C(NR⁸)NR⁸R⁸, ff) —S(O)_(p)R⁸,gg) —SO₂NR⁸R⁸, hh) C₁₋₆ alkyl, ii) C₂₋₆ alkenyl, jj) C₂₋₆ alkynyl, kk)C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and ll) 3-14membered saturated, unsaturated, or aromatic heterocycle comprising oneor more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, wherein any of hh)-ll) optionally is substitutedwith one or more moieties selected from the group consisting of R⁸, F,Cl, Br, I, —CF₃, —OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —C(O)NR⁸R⁸, —NR⁸C(O)R⁸, —OC(O)NR⁸R⁸, —NR⁸C(O)OR⁸,—NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸, —OC(S)R⁸, —C(S)NR⁸R⁸, —NR⁸C(S)R⁸,—OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸, —NR⁸C(S)NR⁸R⁸, —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸, and—S(O)_(p)R⁸; R⁸, at each occurrence, independently is selected from thegroup consisting of: a) H, b) C₁₋₆ alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆alkynyl, e) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, f)3-14 membered saturated, unsaturated, or aromatic heterocycle comprisingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, g) —C(O)—C₁₋₆ alkyl, h) —C(O)—C₂₋₆ alkenyl, i)—C(O)—C₂₋₆ alkynyl, j) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromaticcarbocycle, k) —C(O)-3-14 membered saturated, unsaturated, or aromaticheterocycle comprising one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C₁₋₆ alkyl, m)—C(O)O—C₂₋₆ alkenyl, n) —C(O)O—C₂₋₆ alkynyl, o) —C(O)O—C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, and p) —C(O)O-3-14 memberedsaturated, unsaturated, or aromatic heterocycle comprising one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, wherein any of b)-p) optionally is substituted with one or moremoieties selected from the group consisting of F, Cl, Br, I, —CF₃, —OH,—OCH₃, —SH, —SCH₃, —CN, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —C(O)CH₃,—C(O)OCH₃, —C(O)NH₂, —NHC(O)CH₃, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂, and—S(O)_(p)CH₃; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and p, ateach occurrence, independently is 0, 1, or 2, and wherein the compounddoes not have the formula corresponding to any of the structures listedin Table
 1. 2. The compound according to claim 1, having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, B, L, M, R¹, R², R³, m, and n are defined as described in claim
 1. 3.The compound according to claim 2, having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, B, L, M, R¹, R², R³, m, and n are defined as described in claim
 1. 4.The compound according to claim 1, wherein A is selected from the groupconsisting of phenyl and pyridyl; B is selected from the groupconsisting of phenyl and pyridyl; m is 0, 1, or 2; and n is 0, 1, or 2.5. The compound according to claim 1, wherein A-B is:

wherein A, R², and n are defined as described in claim
 1. 6. Thecompound according to claim 5, wherein A-B is:

wherein A is defined as described in claim
 1. 7. The compound accordingto claim 5, wherein A-B is:

wherein A is defined as described in claim
 1. 8. The compound accordingto claim 1, wherein A-B is:

wherein B is defined as described in claim
 1. 9. The compound accordingto claim 1, wherein A-B is:

wherein B is defined as described in claim
 1. 10. The compound accordingto claim 1, wherein R³ is —NHC(O)R⁴.
 11. The compound according to claim10, wherein R⁴ is —CH₃.
 12. The compound according to claim 1, whereinR³ is:


13. The compound according to claim 1, having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, B, L, M, R¹, R², m, and n are defined as described in claim
 1. 14.The compound according to claim 1, having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinA, L, M, R¹, R³, and m are defined as described in claim
 1. 15. Apharmaceutical composition comprising one or more compounds according toclaim 1 and a pharmaceutically acceptable carrier.
 16. A method oftreating an infection, disease, or disorder in a mammal comprising thestep of administering to the mammal an effective amount of one or morecompounds according to claim 1, wherein the infection, disease, ordisorder is selected from microbial infection, fungal infection,parasitic infection, proliferative disease, viral infection,inflammatory disease and gastrointestinal motility disorder.
 17. Amethod of treating a disorder in a mammal comprising the step ofadministering to the mammal an effective amount of one or more compoundsaccording to claim 1 thereby to ameliorate a symptom of the disorder,wherein the disorder is selected from the group consisting of: a skininfection, nosocomial pneumonia, post-viral pneumonia, an abdominalinfection, a urinary tract infection, bacteremia, septicemia,endocarditis, an atrio-ventricular shunt infection, a vascular accessinfection, meningitis, surgical prophylaxis, a peritoneal infection, abone infection, a joint infection, a methicillin-resistantStaphylococcus aureus infection, a vancomycin-resistant Enterococciinfection, a linezolid-resistant organism infection, and tuberculosis.18. A medical devise containing one or more compounds according toclaim
 1. 19. A process for preparing a compound according to claim 1,comprising the step of reacting a compound of formula (I):

with a compound of formula (II):

in a solvent in the presence of a base and a palladium catalyst, whereinQ is a boronate having the formula —BY₂, wherein Y, at each occurrence,independently is selected from the group consisting of: a) —OH, and b)—O—C₁₋₄ alkyl, alternatively, two Y groups taken together are selectedfrom the group consisting of: a) —OC(R⁴)(R⁴)C(R⁴)(R⁴)O—, and b)—OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—, alternatively, two Y groups taken togetherwith the boron to which they are bound comprise a BF₃ alkali metal salt;Z is selected from the group consisting of: a) I, b) Br, c) Cl, and d)R⁴OSO₃—; and A, B, L, M, R¹, R², R³, R⁴, m, and n are defined asdescribed in claim 1.